Cu-Catalyzed silylation of alkynes: A traceless 2-pyridylsulfonyl controller allows access to either regioisomer on demand

Article abstract of DOI:10.1021/jacs.5b02667

The Cu-catalyzed silylation of terminal and internal alkynes bearing a 2-pyridyl sulfonyl group (SO₂Py) at the propargylic position affords a breadth of vinyl silanes in good yields and with excellent regio- and stereocontrol under mild conditi

Full text of DOI:10.1021/jacs.5b02667

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Article
Cu-Catalyzed Silylation of Alkynes: A Traceless 2-Pyridylsulfonyl
Controller Allows Access to either Regioisomer on Demand
Alfonso Garcia-Rubia, José A. Romero-Revilla, Pablo
Mauleón, Ramon Gomez Arrayas, and Juan C. Carretero
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b02667 • Publication Date (Web): 08 May 2015
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Cu-Catalyzed Silylation of Alkynes: A Traceless 2-Pyridylsulfonyl
Controller Allows Access to either Regioisomer on Demand
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Alfonso García-Rubia, Jose A. Romero-Revilla, Pablo Mauleón,* Ramón Gómez Arrayás,* and Juan C.
Carretero*.
Universidad Autónoma de Madrid (UAM). Cantoblanco 28049 Madrid (Spain)
KEYWORDS: silylcupration · Cu-catalysis · hydrosilylation · vinyl silane · 2-pyridyl sulfone
ABSTRACT: The Cu-catalyzed silylation of terminal and internal alkynes bearing a 2-pyridyl sulfonyl group (SO2Py) at the propargylic
position affords a breadth of vinyl silanes in good yields and excellent regio- and stereocontrol under mild conditions. The directing
SO2Py group is essential in terms of reaction efficiency and chemoselectivity. Importantly, this group also provides the ability to re-
verse the regiochemical outcome of the reaction, opening the access to either regioisomer without modification of the starting sub-
strate by virtue of an in situ base-promoted alkyne to allene equilibration which takes place prior to the silylcupration process. Fur-
thermore, removal of the directing SO2Py allows for further elaboration of the silylation products. In particular, a one-pot tandem
alkyne silylation/allylic substitution sequence, in which both steps are catalyzed by the same Cu species, opens up a new approach for
the access to either formal hydrosilylation regioisomer of unsymmetrical aliphatic-substituted internal alkynes from propargyl sulfones.
facilitated the extension of some of the prototypical B2Pin2
INTRODUCTION
reactivity to the hydrosilylation of alkynes via silyl-Cu complex-
es (it is only the R3Si group in the transmetalation with LCuOR
that is transferred to an acceptor molecule).[8-14] However, the
regioselectivity trends observed for the borylation of alkyl-
alkynes do not appear to be extensive to silylation. For instance,
in a recent elegant example of sequential silylation/borylation
of terminal alkynes catalyzed by Cu-NHC complexes,[9] Hoveyda
observed exclusive generation of the -hydrosilylation isomer
(linear), regardless of the electronic attributes of the alkyne
substituent (Scheme 1a), which is in sharp contrast with the
analogous borylation process.[5,6] In 2011, Loh described the
complementary highly -regioselective synthesis of vinylsilanes
(branched) through PhMe2Si-BPin addition to alkyl-substituted
terminal alkynes catalyzed by a Cu-bulky phosphine complex
(Scheme 1a).[10] More recently, Oestreich has reported a linear-
selective Cu-catalyzed PhMe2Si-BPin-silylation of terminal al-
kynes without added ligand, in which the solvent was found to
greatly influence the regioselectivity.[11]
However, even after these important advances, the regiocon-
trolled silylation of internal alkynes still represents a major
challenge. Only recently have appeared the first successful re-
ports on the Cu-catalyzed silylation of internal alkynes, albeit
high regiocontrol has only been achieved in substrates with a
marked electronic bias such as conjugated electron-deficient
internal alkynes (e.g., propyolates),[12] 1-aryl-1-alkynes or 1,3-
enynes,[11,13] (Scheme 1b). To the best of our knowledge, a gen-
eral method to achieve the direct catalytic hydrosilylation of
unbiased unsymmetrical aliphatic-substituted internal alkynes
with high regiocontrol is yet to be reported. Moreover, the
ability to reverse the regiochemical outcome of the reaction
without modification of the starting substrate or the catalyst,
thereby providing access to both regiocomplementary alkyne
Vinyl silanes have found widespread applications in modern
synthetic organic chemistry as versatile building blocks, and
methods for their production continue to be an area of unques-
tionable interest.[1] The catalytic hydrosilylation of alkynes is
arguably the most powerful and direct reaction for the synthesis
of these reagents since it offers potential for complete control of
the regio- and stereoselectivity.[2] While most of the examples
reported in the literature have focused on the hydrosilylation of
terminal alkynes, internal alkynes have received considerably
less attention due to their lower reactivity and the inherent
difficulty to achieve useful regiocontrol. Indeed, the problem of
regioselectivity truly comes to the fore when unbiased unsym-
metrical (internal) alkynes with close similarity in terms of
electronic and steric properties of the acetylenic substituents are
employed. It is thus of great importance to broaden the ap-
plicability of alkyne metallation reactions to this type of sub-
strates, as it would open up new ground for design approaches.
The development of methods that result in a formal umpolung
of the standard electrophilic reactivity of boron reagents to
nucleophilic[3] (boryl-Cu complexes obtained by transmetalation
of B2Pin2 with LCuOR species), independently reported in
2000 by the Miyaura and Hosomi groups,[4] has fueled the
invention of new technologies directed at solving the issue of
regioselectivity in the hydrometallation of alkynes. Work pio-
neered by the Hoveyda laboratories using this nucleophilic
boryl-Cu species has inspired solutions for the regioselective
hydroborylation of alkynes, both terminal[5] and internal,[6] in
which the introduction of directing atoms at the propargylic
position is crucial to effect regiocontrol.
The development of a family of boron-silicon reagents by
Suginome and co-workers (most notably PhMe2SiBPin)[7] has
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silylation products, would notably expand further the structural
for Cu-catalyzed borylations of propargylic carbonates,[19] and by
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scope of vinyl silane synthesis. Literature precedents for tuning
of regioselectivity in metalation of alkynes are rare and typically
rely on structural modification of the starting substrate or lig-
and control;[15] however, an emerging alternative for controlling
regioselectivity based on the use of alkynes as allene surrogates
is receiving increasing attention from the synthetic communi-
ty.[16]
Oestreich in the Cu-catalyzed silylation of propagylic chlorides
and phosphates,[20] the use of functional groups with high leav-
ing group abilities such as phosphate or carbonate (entries 4
and 5, respectively) resulted in formation of the corresponding
silyl-allene. Finally, we observed that the installation of sulfur-
based moieties at the propargylic position had a marked effect
in regioselectivity, although only sulfones afforded hydrosilylat-
ed compounds in high yields (entries 7-9). Among them, the
use of 2-PySO2 (entry 8) resulted in almost exclusive -silylation
and 78% of pure isolated product 10. Although the precise role
of the 2-PySO2 group in this transformatiojn is unclear at this
stage, this result suggests that the 2-pyridyl unit has an addi-
tional effect on regiocontrol that enhances the primary effect of
the sulfonyl group (entry 7). This secondary effect could be due
to the potentially coordinating ability of the 2-pyridiyl unit
since the use of the electronically related 4-PySO2 group led to
a lower regioselectivity level (entry 9).
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Scheme 1. Control of regioselectivity in the Cu-catalyzed hy-
drosilylation of alkynes.
Table 1. -Silylation of propargylic substituted 2-hexynes.
Conv. (%)b allene b Yield (%)c
Entry FG (alkyne)
1
2
3
4
5
6
7
8
9
OH (1)
95
43:57:<2
38:62:<2
19:81:<2
<2:<2:>98
<2:<2:>98
<2:>98:<2
15:85:<2
4:96:<2
33
62d
60

We recently described the development of a two-step protocol
to access formal hydroboration products of unbiased internal
alkynes.[6a,17] This strategy relies on the use of a propargylic
SO2Py group[18] as a traceless element of site-selectivity control
to produce one specific regioisomer. We envisioned that our
findings could be brought further to bear on the formulation of
unique methods that would facilitate switching of the regio-
chemistry of a given reaction on demand, starting from the
same substrate, by simply changing the reaction conditions (e.g.,
by virtue of an in situ base-promoted alkyne to allene isomeriza-
tion). Herein, we demonstrate the successful implementation of
this concept applied to the - and -regioselective silylation of
alkynes using the SO2Py as powerful element of regiochemistry
and reactivity control, as well as a flexible handle for further
elaboration of the resulting products, which enables ready
regiodivergent access to structurally diverse vinyl silanes
(Scheme 1c).
OTIPS (2)
NHTs (3)
>98
80
OPO(OEt)2 (4) 35
OCO2Me (5)
S(2-Py) (6)
87
9
64

SO2Ph (7)
74
>98
85
60
78
68
SO2(2-Py) (8)
SO2(4-Py) (9)
22:78:<2
aReaction conditions: Alkyne (1.0 equiv), PhMe2SiBPin (1.1
equiv), CuCl (10 mol %), PCy3 (11 mol %), NaOtBu (12 mol %),
1
MeOH (2 equiv), toluene, rt, 2 h. bDetermined by H NMR in the
c
crude mixture. Isolated yield in major product after chromatog-
raphy. dObtained as an inseparable mixture of regioisomers.
Influence of the ligand. During the development of the
hydrosilylation reaction, we noticed that the use of a proper
phosphine ligand was crucial in terms of both reactivity and
selectivity. This observation was in accordance with literature
precedents. For example, in the context of Cu-catalyzed silyla-
tion of terminal alkynes, the utilization of an electron-rich and
bulky monophosphine ligand such as PtBu3 and Johnphos[21]
was found to be crucial by the group of Loh to achieve high
levels of reactivity and branched()-selectivity,[10a] whereas exclu-
sive linear()-selectivity was achieved by Hoveyda’s group using
copper complexes of NHC ligands (SIMes).[5a,5b] To evaluate the
effect of the ligand in the silylation of the model internal pro-
pargyl sulfone 8, a ligand screen was performed which corrobo-
rated that PCy3 was optimal in fulfilling the subtle balance of
steric and electronic requirements for achieving high reactivity
and regiocontrol in this reaction (Table 2). The IMes NHC
RESULTS AND DISCUSSION
Optimization studies: search for a convenient directing
group. At the outset of our studies, we prepared several inter-
nal alkynes bearing polar functions at the propargylic position
that could act as directing groups, and explored their reactivity
under standard conditions extrapolated from borylation prece-
dents[5,6] and using Suginome’s reagent PhMe2SiBPin as the
silicon source (substrates 1-9, Table 1). In contrast to the high
regioselectivity observed in hydroborylations,[5,6] the hydrosilyla-
tion of substrates bearing typical O- and N-based functional
groups at the propargylic position, such as OH (entry 1), the
bulkier OTIPS (entry 2), or tosylamino (entry 3), afforded silyla-
tion products in high conversion but poor regioselectivities. In
agreement with observations reported by Sawamura and Szabó
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ligand was poorly effective, providing the hydrosilylation prod-
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uct 10 in 40% conversion and modest levels of -regioselectivity
(/ = 75:25, entry 1). Unexpectedly, the saturated analogue
SIMes ligand was totally ineffective (no reaction observed, entry
2). The use of Ph3P improved both yield (71%) and regioselec-
tivity (/ = 86:14) of the vinyl silane 10, albeit to unpractical
levels (entry 3). Phosphines with more electron-donating ability
such as P(2-furyl)3 or PnBu3 slightly improved further the -
selectivity to 90%, but at the cost of a decline in reactivity
(<50% conversion, entries 4 and 5). Finally, whereas PCy3 pro-
vided full conversion and excellent -regioselectivity (/ =
96:4, entry 6), the bulkier PtBu3 was found to be much less
effective in terms of both reactivity (26% conversion) and regi-
oselectivity (= 16:84; entry 7), thus suggesting that the steric
hindrance of the ligand is also an important factor for catalytic
activity and selectivity.
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aSame reaction conditions as in Table 1; reaction time 2-3 h. In
1
Table 2. -Silylation of propargylic substituted 2-hexynes.
parenthesis, regioselectivity ( ratio) determined by H NMR in
the crude mixtures. Isolated yield for the mixture of regioisomers.
SO2Py = 2-PySO2
We also examined the feasibility of extending this reactivity
profile to propargyl 2Py-sulfones derived from terminal alkynes.
This was indeed the case and several terminal propargylic sul-
fones reacted cleanly under the optimized conditions to afford
the corresponding -silylated allylic sulfones (29-32) in good
yields and satisfactory regioselectivities (ranging from 90:10 to
>97:<3, Scheme 2).
Entrya
Ratiob
Conversion (%)b
Ligand (L)
IMesc
SIMesd
1
2
3
4
5
6
7
25:75

40
<5
71
28
47
>98
26
PPh3
14:86
9:91
P(2-furyl)3
P(nBu)3
PCy3
Scheme 2. Extension of the -silylation to terminal alkynes
10:90
4:96
P(tBu)3
16:84
aReaction conditions: Alkyne (1.0 equiv), PhMe2SiBPin (1.1
equiv), CuCl (10 mol %), PCy3 (11 mol %), NaOtBu (12 mol %),
1
MeOH (2 equiv), toluene, rt, 3 h. bDetermined by H NMR in the
c
crude mixture. IMes:1,3-bis-(2,6-diisopropylphenyl) imidazolinium
d
chloride.
SIMes: 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-
imidazol-2-ylidene. SO2Py = 2-PySO2
Studies towards regioselectivity switch: from - to -
selective silylation. Once established an efficient silylation
protocol that provides high control of both -regioselectivity
and stereoselectivity across a broad range of substrates, our
attention was shifted to developing a method with the ability to
reverse the regiochemical outcome of the reaction, since it
would provide access to the opposite -regioisomer without
modification of the starting substrate. The accumulated
knowledge on the chemistry of sulfones led us to envision an op-
portunity to invert the regioselectivity of the silylation process:
taking advantage of a well-known isomerization process that trans-
forms propargylic sulfones (I) into allenyl sulfones (II, Scheme
3)[22]. Allenes have been shown to undergo hydrosilylation and
hydroborylation processes, with the regiochemistry of these pro-
cesses being significantly affected by substitution.[12c,23] In particu-
lar, previous work in Cu-catalyzed hydroboration[23c] and hydros-
ilylation[12c] of electron-deficient allenes has shown that the
electron density bias imposed by the electron withdrawing
group directs the exclusive installation of the boryl or silyl moi-
ety on the central allene carbon, leading to a stabilized allyl Cu-
enolate intermediate which then undergo protonolysis by
Cu-catalyzed -silylation of propargylic 2-pyridyl sul-
fones. With the optimal catalysis conditions in hand, we next
sought to examine the scope of the alkyne substitution of this
new -silylation protocol. As shown in Table 3, the reaction of a
range of structurally diverse internal propargylic (2-Py)-sulfones
resulted in formation of the corresponding trisubstituted -silylated
allylic sulfones in good yields (products 18-24, 61-80%) and good to
excellent selectivities (/ ratio 77:2397:3). The mild reaction
conditions allow for good compatibility with a variety of functional
groups: substrates bearing primary alkyl bromides, aryl bromides or
potentially coordinating nitriles (products 20, 21, and 22, respec-
tively) were shown to be amenable to the transformation, which
demonstrates the ability of this silylation protocol to generate vinyl
silane products containing synthetically useful functional handles
that might be readily exploited in subsequent transformations. The
reaction was found to be equally effective for the more sterically
congested internal alkynes with branched propargylic substitution
(R2 = Me or nPr, 22-24).
Table 3. -Silylation of internal propargylic 2-pyridyl sul-
fones.a
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ROH. On the basis of these precedents, we reasoned that the
sulfone 34 was exclusively formed after only 20 minutes, as
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putative intermediate allenyl sulfone II would undergo addition
of the Si-Cu complex across the CaCb double bond (instead of
the CbCc centers of the starting propargyl sulfone I), resulting
in the allylic copper intermediate IV, which could find addi-
tional stabilization by coordination of the metal to the pyridyl
nitrogen of the SO2Py group[18] (Scheme 3). If a base-promoted
equilibration between I and II occurs prior to the hydrosilyla-
tion reaction, and assuming that the allene species (II) is more
reactive than the parent alkyne, this regime for reversible al-
kyne-allene interconversion would provide a Curtin-Hammett
scenario, thus enabling a complementary approach for -
selective silylation. Under such conditions, product selectivity
should be largely dependent upon the relative silylation rate
constant of both equilibrating species (I and II) rather than
their relative stability. If successful, this method would provide
access to both regioisomers of the same starting material by
simply switching the reactive species.
opposed to 120 minutes required for the -silylation of the
corresponding propargylic sulfone 18. This result indicates that
the allenyl sulfones are more reactive than the propargylic sul-
fones under our Cu-catalyzed silylation conditions.[25,26]
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Cu-catalyzed -silylation of propargylic 2-pyridyl sul-
fones. With this information in hand, we reasoned that pre-
stirring our substrates in the presence of an equivalent of base
would result in a relatively fast equilibration of the initial pro-
pargylic sulfone to the allenyl sulfone.[27] Assuming that the
allene species are more reactive than the alkyne, this scenario
could enable a new approach for a selective -silylation process.
Gratifyingly, under these reaction conditions, we found that
both terminal and internal alkynes underwent a smooth -
silylation process (Table 4), in which the only products detected
in the reaction mixtures were the desired regio- and diastereo-
merically pure -silylated isomers. When internal alkynes were
used as substrates, the silylation products were obtained as
mixtures of rotamers about the CS/CSi sigma bond (ranging
from 80:20 to 98:2). The high chemoselectivity was also
demonstrated in the -silylation reaction of alkynes bearing
functional groups such as silyl ethers, alkyl chlorides or nitriles
(45, 46, and 47, respectively).
Scheme 3. Propargyl and allenyl (2-Py)sulfones: potential diver-
gent reactivity.
Table 4. -Silylation of propargylic 2-pyridyl sulfones.a
To secure the success of our work plan, two conditions needed
to be fulfilled: firstly, the base required to effect the rearrange-
ment should not inhibit the silylation reaction. Along these
lines, several bases have been shown to be compatible with
Me2PhSiBPin in related transformations.[11] Secondly, the
allene should be more reactive than the corresponding alkyne
in order to shift a hypothetical equilibrium. To examine these
hypotheses, we treated substrates 16 and 18 with several bases
in toluene, and observed that a number of them promoted this
rearrangement; the propargyl/allenyl ratio was shown to de-
pend on the substitution pattern of the starting material: in
particular, we observed that for terminal alkyne 18 the equilib-
rium was completely shifted towards the allene, whereas a 1:1
mixture of species in equilibrium was detected in the case of
internal alkyne 16 (eq 1).[24] Among the bases tested,
NBu4H2PO4 was chosen in light of its very low coordinating
ability, which should not inhibit the formation of the required
copper catalyst. Additionally, its poor nucleophilicity consti-
tutes an additional advantage in terms of functional group
tolerance.
aReaction conditions: Alkyne (1.0 equiv), NBu4H2PO4 (1.0
equiv), toluene, rt for internal alkynes or 50 °C for terminal al-
kynes, 1 h; then, PhMe2SiBPin (1.0-1.5 equiv), CuCl (10 mol %),
PCy3 (11 mol %), NaOtBu (12 mol %), MeOH (2 equiv), rt or 50
Strong support for the second premise was found in silylation
experiments carried out using preformed allenyl sulfone 33.
When this compound was submitted to the optimized silylation
reaction conditions (eq. 2), the corresponding -silylated allyl
b
1
°C. In parenthesis, ratio of rotamers determined by H NMR in
the crude mixtures. SO2Py = 2-PySO2
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The presence of rotamers in equilibrium was unambiguously
Assuming the accepted mechanism of coordination/syn-
addition of the Si-Cu complex to the unsaturated substrate, the
formation of the diastereomer 34-D2 would be largely unex-
pected if an equilibration of rac-33-D to the corresponding
alkyne followed by silylcupration on the latter intermediate had
taken place. In addition, hydrosilylation of substrate 33 in the
presence of MeOD resulted in significant levels of deuterium
incorporation at the allylic position, whereas no deuterium
scrambling was detected at the vinylic positions (product 34-D3):
this observation is consistent with the participation of the pro-
posed pyridinium-stabilized Cu intermediate IV (Scheme 4b).[22]
Conversely, the hydrosilylation of alkyne 18 in the presence of
MeOD allowed the deuterium interception of the presumed
intermediate III, furnishing the -silylated product 29-D with
significant incorporation of deuterium at the -vinylic position.
Notably, hydrogen was completely retained at the methine
adjacent to the sulfonyl group, which strongly supports the
participation of the proposed intermediate III. The partial H/D
exchange observed at the terminal vinylic position is ascribable
to partial deprotonation of the acidic acetylenic position under
the basic reaction conditions prior to silyl-cupration of the
alkyne, which also might justify the incomplete deuteration at
C2. In agreement with this proposal, when propargyl sulfone 18
was subjected to the standard reaction conditions (tBuOCu-
PCy3) in the absence of the Si-B reagent and in the presence of
MeOD, 17% deuterium incorporation at the acetylenic posi-
tion was observed. Importantly, except for the latter case, no
deuterium scrambling was observed in those positions not
directly involved in the metalation step for each proposed
mechanism (vinylic positions in the reaction from allene 33 and
allylic position in the reaction from alkyne 18, Scheme 4),
which strongly supports the notion that both regiochemistry
patterns originate from different reaction intermediates.
determined by NMR studies on compound 42 (Figure 1). In
particular, 1H NMR studies at variable temperatures resulted in
coalescence of those peaks attributed to equivalent protons at
temperatures above 85 ºC. Additionally, cooling back to 25 ºC
resulted in recovery of exactly the same ratio of rotamers, while
no signs of decomposition were observable in the spectrum.
Furthermore, the existence of an equilibrium between the two
rotamers in 42 was supported by the observation of strong
exchange cross-peaks (EXSY) between equivalent protons of
each rotameric pair in a 2D NOESY experiment (signals de-
rived from NOE or from chemical exchange will appear in
different phases).[28]
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11
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49
50
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60
Scheme 4. D-labeling studies on the reaction mechanism.
SiMe2Ph
SO2Py
SiMe2Ph
SO2Py
D
H
D
H
= 100% D
= 100% H
1
[Si-Cu]
MeOH
3
SO2Py
nPr
H
D
+
(a)
•
2
nPr
nPr
D
H
34-D1
34-D2
33 D
rac-
-
O
SO2Py
O
S
N
H
PhMe2Si
H
nPr
[Si-Cu]
SO2Py
nPr
(b)
•
[Cu]
R2
H/D
H
MeOD
H
H
H
[Si]
H/D = 45:55
34-D3
IV
33
H/D = 68:32
H/D
SO2Py
nPr
SO2Py
FG
R2
H
Figure 1. Olefinic and allylic peaks attributed to rotamers in com-
pound 42. (i) Coalescence of at higher temperature. (ii) Exchange
cross-peaks observed in a 2D NOESY experiment.
[Si-Cu]
H
(c)
nPr
[Si]
III
H
H
PhMe2Si
H/D
H:D = 58:42
MeOD
H
[Cu]
18
29 D
-
Mechanistic insights: isotope tracer experiments. Support
for the participation of the catalytic intermediate species IV and
III in the -silylation via allene and -silylation via alkyne, re-
spectively (see Scheme 2), was obtained from deuterium label-
ing experiments shown in Scheme 4. Firstly, a 1:1 mixture of
deuterated diastereoisomers across the terminal double bond
(34-D1 + 34-D2) was obtained after 20 minutes when the deu-
terated allene rac-33-D was submitted to the standard reaction
conditions (Scheme 4a), adding additional weight to our previ-
ous observations depicted in equation 2. The formation of both
diastereomers in equal amounts is consistent with a silylcupra-
tion process at C1 and C2 of the proposed allene intermediate.
Further elaboration of vinyl silanes: selective transfor-
mations on vinyl silanes/allylic sulfones. In hopes of illus-
trating further the utility of the method described above, we
looked into representative transformations of vinyl silanes and
allylic sulfones which would selectively remove either one of
these functional groups. Firstly, the sulfonyl group in the silyla-
tion products could be smoothly removed without interference
by the silicon moiety by standard treatment with Na(Hg) with
concomitant migration of the olefin to give rise to synthetically
useful stereochemically enriched (or pure) allyl and vinyl silanes
(Scheme 5, products 48 and 49, respectively).
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Scheme 5. Selective removal of the SO2Py group.
Ensuring high conversion in the overall process required, how-
4
5
6
7
8
9
ever, careful adjustments of the excess of MeOH used in the
silylation step and the amount of Grignard reagent needed for
the allylic substitution. We were glad to find that using 2.0
equiv of MeOH and 2.0 equiv of RMgX, the tandem -
silylation/allylic substitution was productive for the model
reaction of alkyne 18 using PhMgBr as Grignard reagent to give
cleanly the SN2-type product 54, resulting from -addition to
the unsymmetrical allyl sulfone intermediate, with complete
levels of regiocontrol (>98% -selectivity, Table 5). The ob-
served regioselectivity can be attributed to the high steric de-
mand at the -allylic position imposed by the R3Si group (attack
favored at the less sterically congested allylic terminus).
10
11
12
13
14
15
16
17
18
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21
22
23
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29
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34
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42
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
In our exploratory studies of the selective reactivity of the sili-
con group, we observed that treatment of vinyl silane 29 with a
strong base (KHMDS), followed by addition of benzaldehyde,
resulted in formation of sulfonyl diene 50 in 74% yield by
formal Peterson olefination (Scheme 6). Interestingly, the stere-
ochemistry of the process was easily inverted by switch to
LiHMDS in the presence of the crown ether 12-crown-4 (prod-
uct 51, 69%). Other studies performed along these lines in-
volved the transformation of the vinyl silanes obtained above in
other practical functionalities. For example, vinyl silane 10 was
smoothly converted in silanol 52 by treatment with TfOH in
cold DCM.[29] The utility of silanols as partners in Hiyama
couplings has been extensively studied by Denmark.[30] Also,
treatment of 10 with bromine in DCM resulted in formation of
vinyl bromide 53 in good yield and with complete stereocontrol
(inversion of the E/Z stereochemistry).[31]
Table 5. One-pot regio- and stereoselective synthesis of di- and
trisubstituted vinyl silanes.a,b
Scheme 6. Transformations that involve removal of the
Si(Me)2Ph group.
SO2Py
SO2Py
nPr
b)
a)
PhMe2Si
SO2Py
nPr
Ph
Br
nPr
50, 74%
29
51, 69%
Ph
SO2Py
SO2Py
SO2Py
c)
d)
nPr
nPr
a
Reaction conditions: Alkyne (1.0 equiv), PhMe2SiBPin (1.1
SiMe2Ph
10
SiMe2OH
52, 83%
nPr
equiv), CuCl (10 mol %), PCy3 (11 mol %), NaOtBu (12 mol %),
MeOH (2 equiv), toluene, rt, 2 h; then, ArMgX (2 equiv), rt, 2-16h.
bIsolated yields after flash chromatography. SO2Py = 2-PySO2
53, 78%
Conditions: a) KHMDS, DME, 78 ºC, 30 min; then, PhCHO.
b) LHMDS, 12-crown-4, DME, 78 ºC, 30 min; then, PhCHO. c)
TfOH, CH2Cl2, 0 ºC, 1 h. d) Br2, CH2Cl2, rt. SO2Py = 2-PySO2
By following the one-pot protocol, the scope of this reaction
was next explored (Table 5). Other terminal alkynes with linear
or branched substituents at the propargylic position (R2) proved
to be equally effective (55 and 56, 82% and 79%, respectively).
To our delight, this tandem reaction is not limited to terminal
alkynes. Internal alkynes, with or without branched propargylic
substitution, were also found to be fully compatible, affording
the corresponding products in good yields while preserving the
complete -regiocontrol in the allylic substitution step (57-63,
60-75%). A sensitive alkyl bromide substitution was tolerated
under the present conditions (60, 66%). A variety of aryl Gri-
gnard reagents of different steric and electronic properties (64-
70, 56-79%), including heteroaromatics (68, 75%) are applica-
ble. The current tandem one-pot reaction produced structurally
elaborated vinyl silanes in good yields. In all examples described
in Table 5 (17 cases studied), a single regioisomer (>98% -site
selectivity in the silylation reaction and >98% -site selectivity
in the allylic substitution) and diastereoisomer (>98% E-
One-pot formal access to hydrosilylation products of
unbiased alkynes. In accordance with our desired goal of
accessing formal hydrosilylation products of unsymmetrical
aliphatic-substituted internal alkynes, we next focussed on a
potential Cu-catalyzed allylic substitution reaction with Gri-
gnard reagents, similar to the one reported by us for vinyl
boronates.[17] In this case, however, we pondered the feasibility
of a condensed tandem one-pot silylation/allylic alkylation
sequence starting directly from the alkyne instead of using the
preformed vinyl-metal species, as it would significantly improve
the synthetic value of this process while simplifying the reaction
setup. The main challenge to be solved is that both steps need
to be compatible under the same Cu-catalyst system. If such
requirement is met, simple addition of a Grignard reagent to
the reaction vessel on completion of the silylation step would in
principle enable tandem silylation-arylation.
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stereoselectivity) of the product is formed (products 54-70, 56-
4
82% yield).
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6
7
8
This one-pot silylation/allylic substitution sequence is also
compatible with the base-promoted -silylation via allene, even
though the presence of stoichiometric amounts of NBu4H2PO4
makes this process more challenging. Interestingly, in this case
the regiochemical outcome of the allylic substitution step was
reversed, providing exclusively the SN2’-type product, as a result
of the attack of the Grignard reagent to the -terminus of the
allyl sulfone intermediate (>98% -selectivity Table 6). The lack
of a sterically hindered silyl group at the -allylic position could
be the reason behind this SN2’-type selectivity, which on the
other hand is typically observed in Cu-catalyzed allylic substitu-
tions.[32] A variety of trisubstituted vinyl silanes with different
substitution pattern were obtained regioisomerically pure with
acceptable yields in this protocol (products 71-76, 63-75%
yields). The compatibility with heteroarenes at the substrate was
remarkable (product 71, 75%). Unfortunately, however, the
hydrosilylation products were obtained with consistently lower
stereoselectivity, the E/Z ratio ranging from 1:1 to 5.7:1. Except
for one case (product 71), no significant improvement of stere-
ocontrol could be obtained by lowering the temperature (down
to 78 °C). The different levels of stereoselectivity observed for
both processes can be attributed to the divergence in the reac-
tion mechanism (formal SN2 versus SN2’).
CONCLUSIONS
In summary, we report on a general and practical method for
the regio- and stereocontrolled synthesis of di- and trisubstitut-
ed vinyl silanes by Cu-catalyzed hydrosilylation of both internal
and terminal alkynes. The use of a SO2Py group at the propar-
gylic position is essential in three ways: firstly, it controls the
reactivity of the system, preventing alternative reaction path-
ways such as nucleophilic displacement of the directing group;
secondly, it enables an alkyne/allene rearrangement that results
in efficient control of the regioselectivity of the hydrosilylation
process; thirdly, its formal elimination promotes a series of
useful transformations, even in a one-pot fashion. In particular,
we have shown, for the first time, a tandem silylation/allylic
arylation of propargyl sulfones, using the same Cu-catalyst to
access in a single operation novel vinyl sylanes that cannot be
accessed directly from dialkyl alkynes. The overall transfor-
mation can be accomplished in the presence of a wide range of
functional groups. The wide scope highlights the validity of the
method to construct, in a one-pot operation, a variety of trisub-
stituted vinyl silanes having various substitution patterns from
simple propargyl sulfones. This work thus contributes to the
emerging use of alkynes as allene surrogates in transition metal-
catalyzed reactions as a strategy for selectivity control.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 6. Extension to the one-pot regio- and stereoselective
silylation/allylic substitutiona,b
EXPERIMENTAL SECTION
General methods. Dichloromethane, toluene, acetonitrile, and
tetrahydrofuran were taken from a PureSolv MD purification
system. Sodium amalgam [Na(Hg)] 6% was prepared following a
reported procedure.[33] Metal precatalysts, Grignard reagents
and mCPBA (≤77% purity) were purchased from commercial
sources and used without further purification. All reactions
were carried out under inert atmosphere, unless otherwise
noted.
Typical procedure for the -silylation of propargylic sulfones.
CuCl (2.0 mg, 0.020 mmol, 10 mol %) was placed in a
Schlenck tube. The tube was purged and backfilled with argon.
Then was added dry toluene (0.7 mL), tri-cyclohexyl-phosphine
(20 % in toluene, min 88 %) (50 l, 0.022 mmol, 11 mol %)
and NaOtBu (2M in THF) (12 L, 0.024 mmol, 12 mol %) and
the solution was allowed to stir at 22 °C for five minutes. Silyl-
borane reagent (60 L, 0.22 mmol, 1.1 equiv) was added to the
solution, causing it to turn dark brown immediately. The mix-
ture was allowed to stir at 22 °C for 5 min under an argon
atmosphere. The corresponding propargylic sulfone (0.2 mmol,
1.0 equiv) dissolved in toluene (0.5 mL), and MeOH (17 L,
0.4 mmol, 2 equiv) were sequentially added through syringes.
The resulting mixture was allowed to stir at 22 °C until no
starting material was detected (TLC monitoring, 2-16 h). Then,
the reaction was quenched by passing the mixture through a
short plug of celite and silica gel, and then eluted with DCM (3
× 4 mL). The filtrate was concentrated in vacuo and purified by
silica gel chromatography.
aReaction conditions: Alkyne (1.0 equiv), NBu4H2PO4 (1.0
equiv), toluene, rt for internal alkynes or 50 °C for terminal al-
kynes, 1 h; then, PhMe2SiBPin (1.0-1.5 equiv), CuCl (10 mol %),
PCy3 (11 mol %), NaOtBu (12 mol %), MeOH (2 equiv), rt or 50
°C; then, ArMgX (2 equiv), rt, 2-16h. bYields after flash chromatog-
raphy. c Reaction performed at 78 ºC. SO2Py = 2-PySO2
Finally, the facile silicon-bromine exchange process described
for compound 52[30] was successfully applied to the synthesis of
non-functionalized, trisubstituted, vinyl bromides 77 and 78 in
good yields and complete stereocontrol (eq 3). At this point it is
important to note that, in spite of the significance of alkenyl
halides as versatile coupling partners in transition metal cata-
lyzed cross-coupling reactions and as precursors to a wide range
of organometallic reagents, the synthesis of alkenyl halides,
especially those involving trisubstituted alkenes in a stereode-
fined manner is challenging.
Typical procedure for the -silylation of propargylic sulfones.
The corresponding propargylic sulfone (0.2 mmol, 1.0 equiv)
and (NBu4)H2PO4 (67.8 mg, 0.2 mmol, 1.0 equiv) were placed
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(4) (a) Ito, H.; Yamanaka, H.; Tateiwa, J.-i.; Hosomi, A. Tetrahedron
Lett. 2000, 41, 6821; (b) Takahashi, K.; Ishiyama, T.; Miyaura, N.
Chem. Lett. 2000, 982.
in a Schlenck tube. The Schlenck tube was purged and back-
filled with argon, and dry toluene (1.0 mL) was added. The
mixture was stirred at 50 °C for 1 h. In a separate Schlenck
tube, CuCl (2.0 mg, 0.020 mmol, 10 mol %) was placed. The
Schlenck tube was purged and backfilled with argon. Then, dry
toluene (0.7 mL), tri-cyclohexyl-phosphine (20% in toluene,
min 88%) (50 l, 0.022 mmol, 11 mol %) and NaOtBu (2M in
THF) (12 L, 0.024 mmol, 12 mol %) were sequentially added
and the solution was allowed to stir at 22 °C for five minutes.
Silylborane reagent (90 L, 0.3 mmol, 1.5 equiv) was added to
the solution, causing it to turn dark brown immediately. The
mixture was allowed to stir at 22 °C for 5 min under an atmos-
phere of argon. This solution and MeOH (17 L, 0.4 mmol, 2
equiv) were sequentially added through syringes to the first
Schlenck tube. The resulting mixture was allowed to stir at 50
°C (for internal alkynes) or 22 ºC (for terminal alkynes) until no
starting material was detected (TLC monitoring, 30 min-16 h).
Then, the reaction was quenched by passing the mixture
through a short plug of celite and silica gel, and then eluted
with DCM (3 × 4 mL). The filtrate was concentrated in vacuo
and purified by silica gel chromatography.
(5) (a) Jang, H.; Zhugralin, A. R.; Lee, Y.; Hoveyda, A. H. J. Am.
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(7) (a) Ohmura, T.; Suginome, M. Bull. Chem. Soc. Jpn. 2009, 82, 29;
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Chem. Soc. 2014, 136, 17414.
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For tandem Cu-catalyzed PhMe2Si-BPin-silylation of propiolate esters
and Pd-catalyzed allylation: (d) Vercruysse, S.; Cornelissen, L.; Nahra,
F.; Collard, L.; Riant, O. Chem. Eur. J. 2014, 20, 1834. For Pt-catalyzed
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ASSOCIATED CONTENT
Experimental details as well as spectroscopic and analytical data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
pablo.mauleon@uam.es; ramon.gomez@uam.es; juancar-
los.carretero@uam.es.
ACKNOWLEDGMENT
This work was supported by the Ministerio de Economía y Com-
petitividad (MINECO, CTQ2012-35790) and the European Union
for a Marie Curie Career Integration Grant (to P.M). J. R. and P.M.
thank MINECO for a FPI predoctoral fellowship and a Ramón y
Cajal contract, respectively. Frontier Scientific is gratefully
acknowledged for a generous donation of PhMe2SiBPin.
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also ref. 5a. For controlling regioselectivity by choice of catalytic spe-
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alteration in reversibility of a key mechanistic step, see: (i) Jackson, E.
P.; Montgomery, J. J. Am. Chem. Soc. 2015, 137, 958.
(16) For very recent elegant examples of regioselectivity switch in Ru-
catalyzed functionalization of unsymmetrical aliphatic-substituted
internal alkynes that rely on an in situ catalyst-promoted alkyne-allene
isomerization, see: (a) Chen, Q.-A.; Cruz, F. A.; Dong V. M. J. Am.
Chem. Soc. 2015, 137, 3157. (b) Liang, T.; Nguyen, K. D.; Zhang, W.;
Krische, M. J. J. Am. Chem. Soc. 2015, 137, 3161. See references therein
for further examples of metal-catalyst-promoted in situ alkyne-allene
isomerization.
(23) For the regioselective silyl-cupration of allenes, see: (a) Rae, J.;
Hu, Y. C.; Procter, D. J. Chem. Eur. J. 2014, 20, 13143. For regioselec-
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(24) See SI for a more complete study on the effect of several bases
such as KOAc, NaOtBu, KOtBu, and the effect of temperature.
(25) See SI for experimental details.
(26) After completion of our study, Loh and Xu reported that pre-
formed allenes with electron-withdrawing groups directly attached to
the allene moiety undergo silylation at the internal position (ref. 12c).
(27) A pre-stirring time of 1 h in the presence of 1 equiv of base
(NBu4H2PO4) before addition of the silylating reagent was found to be
necessary for achieving complete -regiocontrol. Nevertheless, even in
the absence of pre-treatment with base a good, albeit not complete, -
silylation regioselectivity was observed in agreement with the higher
reactivity of the allenyl sulfone over the propargyl sulfone. For example,
the -silylation reaction of the internal propargyl sulfone 16 in the
presence of base but with no pre-stirring time (i.e., adding the silyl-
borane reagent at time zero) produced product 39 with a regioselectivi-
ty ratio of  = 90:10.
(28) For other examples of use of this technique for the identifica-
tion of rotamers, see: Rayyan, S.; Fossen, T.; Solheim Nateland, H.;
Andersen Ø. M., Phytochem. Anal. 2005, 16, 334, and references cited
therein.
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4141. For the use of related silanols in Hiyama-Denmark coupling
reactions, see: Anderson, J. C.; Munday, R. H. J. Org. Chem. 2004, 69,
8971.
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(18) For early reports on the metal-coordinating ability of 2-
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