Palladium-catalyzed hiyama couplings of α-silylenoates and α-silylenamides

Article abstract of DOI:10.1021/ol301300r

The Hiyama couplings of both α-silylenoates and α-silylenamides are described. These sensitive substrate classes require particularly specific conditions, employing both appropriate silicon-based species and a silver additive to realize high yields of the coupling products. Regioselective platinum-catalyzed hydrosilylations provide a direct and convenient entry into these stereodefined trisubstituted alkenes.

Full text of DOI:10.1021/ol301300r

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3328–3331
Palladium-Catalyzed Hiyama Couplings of
r-Silylenoates and r-Silylenamides
Douglas A. Rooke and Eric M. Ferreira*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
United States
emferr@mail.colostate.edu
Received May 10, 2012
ABSTRACT
The Hiyama couplings of both R-silylenoates and R-silylenamides are described. These sensitive substrate classes require particularly specific
conditions, employing both appropriate silicon-based species and a silver additive to realize high yields of the coupling products. Regioselective
platinum-catalyzed hydrosilylations provide a direct and convenient entry into these stereodefined trisubstituted alkenes.
Palladium-catalyzed cross-couplings have become an
essential tool in the synthetic chemist’s arsenal. In parti-
cular, the Hiyama coupling is an attractive option because
of the relative stability and low toxicity of the vinylsilane
nucleophiles.1 In this transformation, activated silicon
species are generally necessary for transmetalation to pro-
ceed. This requirement has been achieved most commonly
through either the formation of a pentavalent siliconate
intermediate or the use of a silanol species. These indivi-
dual species, however, are often too labile to be maintained
through synthetic steps, and therefore chemists frequently
employ surrogates that can readily generate the reactive
intermediates via triggering reagents (e.g., fluoride ion).
We recently described the platinum-catalyzed hydrosi-
lylations of internal alkynes, where the electronic effects of
the two substituents primarily governed the addition of
the silicon hydride.2 In particular, high levels of regioselec-
tion were observed using electron-deficient alkynes such
as ynoates and ynamides (Figure 1). As part of assess-
ing the synthetic utility of the hydrosilylation products,
one immediate application we envisioned was the direct
cross-coupling of these electron-deficient vinylsilanes.
Recently, Hosoya reported an effective Hiyama coupling
of electron-deficient triethoxyvinylsilanes.3 Herein, we
present ourstudiesonrelatedcross-couplings, demonstrat-
ing that the appropriate choices of both silane species and
reaction conditions are essential for a successful hydro-
silylation/CÀC bond-formation process.
Figure 1. Pt-catalyzed hydrosilylations of internal alkynes.
The cross-couplings of R-silylenoates and R-silylena-
mides, representative products of our hydrosilylations,
present particularly unique challenges (Figure 2). The
electron-poor vinylsilane should be inherently slower in
transmetalation. With R,β-unsaturated carbonyl sub-
strates, competitive conjugate addition processes could
possibly thwart the target transformation.4 Additionally,
the formation of the anionic siliconate intermediate has the
potential of desilylation, leading to stabilized enolate
(1) For an excellent comprehensive review, see: Chang, W. T.; Smith,
R. C.; Regens, C. S.; Bailey, A. D.; Werner, N. S.; Denmark, S. E. Org.
React. 2011, 75, 213–745.
(2) (a) Rooke, D. A.; Ferreira, E. M. Angew. Chem., Int. Ed. 2012, 51,
3225–3230. (b) Rooke, D. A.; Ferreira, E. M. J. Am. Chem. Soc. 2010,
132, 11926–11928.
(3) Sumida, Y.; Kato, T.; Yoshida, S.; Hosoya, T. Org. Lett. 2012, 14,
1552–1555.
r
10.1021/ol301300r
Published on Web 06/19/2012
2012 American Chemical Society

intermediates that could protonate or participate in other
nucleophilic side reactions.
Scheme 1. Hydrosilylation/Deprotection with Silane 2
Figure 2. Potential complications with R-silicon, R,β-unsatu-
rated nucleophiles.
Indeed, initial experiments based on several of the
established silicon species were ineffective in this context.5
2-Pyridyldimethylsilane was unreactive in our platinum-
catalyzed hydrosilylations of alkynes, even at elevated
temperatures. Both allyl- and benzyldimethylsilane were
competent hydrosilylation agents, affording the R-sily-
lenoates in >90% yield. Unfortunately, however, fluoride-
activated protocols for enabling transmetalation also
caused protodesilylation and other complicating back-
ground reactions.
was likely degrading the silane due to the lability of the
acetal functional group.9 Indeed, Pt(dvds), absent the
chloride counterion, provided substantial improvement,
and theR-silylenoate couldbeobtainedin92% yield and in
11:1 regioselectivity. The benzyl alcohol could then be
revealed under standard methanolysis conditions.10
We were then attracted to a report by Nakao, Hiyama,
and co-workers6 that showed that the (2-hydroxymethyl)-
phenyl group, when attached to silicon, could induce
cross-couplings.7 In these systems, added base enabled
intramolecular attack of the alkoxide to silicon, which
activated the species for subsequent transmetalation. We
anticipated that the mild conditions (K2CO3) would facil-
itate the desired process without the aforementioned
complications.
Hydrosilylations of methyl 2-heptynoate with the
THP-protected benzyl alcohol derivative (2) based on
our previously described conditions for internal alkynes
(cat. PtCl2, silane, CH2Cl2, 23 °C) resulted only in de-
composition of the silane (Scheme 1).8 Zeise’s dimer
([(C2H4)PtCl2]2) was more suitable for this transforma-
tion, although the yields and regioselectivities were still
suboptimal. In both cases, the potential generation of HCl
Scheme 2. Hydrosilylations with 1,1,1,3,5,5,5-Heptamethyltri-
siloxane
With the desired R-silylenoate in hand, we proceeded to
evaluate its cross-coupling potential (Table 1). Early opti-
mization trials, originating from Hiyama’s reported con-
ditions, provided erratic results, with yields in the range of
0À55%. Unfortunately, in even the best cases, protodesi-
lylation and other decomposition pathways plagued the
reaction. A breakthrough was achieved when Ag2O was
employed as the base. Further evaluation of the reaction
parameters revealed that anhydrous dioxane was the
optimal medium, and coupled product 6 could be obtained
in excellent overall yield. Notably, a more difficult cou-
pling partner, electron-rich 4-iodoanisole, was similarly
effective in this Hiyama reaction.
An array of aryl iodides and bromides could be coupled
to the R-silylenoate under these optimized conditions
(Table 2). Elevated temperatures (100 °C) were required
for the formation of sterically hindered alkenes (e.g., 6f) or
alkenes arising from electron rich aryl bromides (e.g., 6i).
In all cases, the Hiyama cross-couplings proceeded in good
to excellent yields.11
(4) β-Silyl-R,β-unsaturated carbonyl compounds have been em-
ployed in a few isolated cases. See: (a) Denmark, S. E.; Kobayashi, T.
J. Org. Chem. 2003, 68, 5153–5159. (b) Shindo, M.; Matsumoto, K.;
Shishido, K. Angew. Chem., Int. Ed. 2004, 43, 104–106. (c) Shindo, M.;
Matsumoto, K.; Shishido, K. Synlett 2005, 176–178.
(5) See the Supporting Information for experimental details.
(6) Nakao, Y.; Imanaka, H.; Sahoo, A. K.; Yada, A.; Hiyama, T.
J. Am. Chem. Soc. 2005, 127, 6952–6953.
(7) For select applications of this silicon species in cross-coupling,
see: (a) Chen, J.; Tanaka, M.; Sahoo, A. K.; Takeda, M.; Yada, A.;
Nakao, Y.; Hiyama, T. Bull. Chem. Soc. Jpn. 2010, 83, 554–569.
(b) Shirbin, S. J.; Boughton, B. A.; Zammit, S. C.; Zanatta, S. D.;
Marcuccio, S. M.; Hutton, C. A.; Williams, S. J. Tetrahedron Lett. 2010,
51, 2971–2974. (c) Nakao, Y.; Chen, J.; Tanaka, M.; Hiyama, T. J. Am.
Chem. Soc. 2007, 129, 11694–11695. (d) Nakao, Y.; Imanaka, H.; Chen,
J.; Yada, A.; Hiyama, T. J. Organomet. Chem. 2007, 692, 585–603. (e)
Nakao, Y.; Ebata, S.; Chen, J.; Imanaka, H.; Hiyama, T. Chem. Lett.
2007, 36, 606–607.
Although the use of silane 2 was generally effective, we
still desired to use a more convenient silicon precursor.
1,1,1,3,5,5,5-Heptamethyltrisiloxane, commercially available
(8) To our knowledge, hydrosilylations using 2 have only been
employed for terminal and symmetrical internal alkynes. See ref 5.
(9) We had observed in our previous substrate analysis that pro-
pargylic alcohols, particularly sensitive to acid-catalyzed ionization,
were also problematic substrates with platinum catalysts bearing chlo-
ride counterions.
(10) This sequence can also be accomplished in a single pot in
comparable yields (∼90%). See the Supporting Information.
(11) Other heteroaryl iodides examined (e.g., 2-iodopyridine, 2-io-
dothiophene, 2-iodofuran) were unreactive under these conditions.
Org. Lett., Vol. 14, No. 13, 2012
3329

Table 1. Hiyama Coupling Conditions Optimization
Scheme 3. Ynamide Hydrosilylation/Hiyama Couplings
of potassium hydrogen fluoride was highly beneficial here;
this very mild source of fluoride presumably assists in silyl
ether cleavage, providing activated silicon species for the
intended transforms. With these conditions, a number
of aryl iodides and bromides could be coupled to the silyl
enoates (Table 3). In general, these reactions were not
quite as effective relative to the examples based on the
(2-hydroxymethyl)phenylsilyl species, but they still af-
forded the desired alkene products in good yields overall.
R,β-Unsaturated amides, accessed via similar hydrosily-
lations of the corresponding alkynes, could also be cross-
coupled efficiently (Scheme 3). Vinylsilanes bearing sec-
ondary, tertiary, and Weinreb amides were all competent
nucleophilic components in these Hiyama couplings. En-
ones, however, remained unable to participate similarly,
suggesting that the stability of the enolate has a significant
role in determining the relative amounts of cross-coupling
and protodesilylation products.
Table 2. Hiyama Couplings Based on R-Silylenoate 4
The crucial role of silver ion in these transformations
was intriguing.13 In the absence of silver, cross-coupling
was observed in modest yields at best.14 We primarily
considered two different rationalizations to explain this
necessity. The silver may be helping to ionize the PdÀX
bond resulting from oxidative addition; the more cationic
metal center would thus be activated for transmetalation.
Alternatively, the silicon species could be transmetalating
directly to silver, and the organosilver is the species that
participates in transmetalation with palladium.15
a Isolated yield. b Reaction temperature: 100 °C.
and relatively inexpensive, appeared ideal for this overall
goal.12 To that end, ynoates 1, 7, and 8 were hydrosilylated
with Pt(dvds) under our optimal conditions, and the
corresponding R-silylenoates were obtained in excellent
yield and regioselectivity (Scheme 2).
When the product R-silylenoates were evaluated in the
Hiyama coupling based on our optimized conditions,
coupling was observed, but reactivity was low (appro-
ximately 30% conversion with 4-iodoanisole). The addition
(13) For examples of the effective use of Ag2O in Hiyama couplings,
see: (a) Hirabayashi, K.; Kawashima, J.; Nishihara, Y.; Mori, A.;
Hiyama, T. Org. Lett. 1999, 1, 299–301. (b) Hirabayashi, K.; Mori, A.;
Kawashima, J.; Suguro, M.; Nishihara, Y.; Hiyama, T. J. Org. Chem.
2000, 65, 5342–5349. (c) Nokami, T.; Tomida, Y.; Kamei, T.; Itami, K.;
Yoshida, J.-I. Org. Lett. 2006, 8, 729–731. (d) Napier, S.; Marcuccio,
S. M.; Tye, H.; Whittaker, M. Tetrahedron Lett. 2008, 49, 3939–3942. (e)
Napier, S.; Marcuccio, S. M.; Tye, H.; Whittaker, M. Tetrahedron Lett.
2008, 49, 6314–6315.
(12) For the use of 1,1,1,3,5,5,5-heptamethyltrisiloxane in hydrosi-
lylations/Hiyama couplings, see: (a) Berthon-Gelloz, G.; Schumers,
(14) (a) Similarly, Hosoya found that AgF was an essential additive
to promote the cross-couplings of the vinyltriethoxysilanes. See ref 3. (b)
Other silver salts (AgF, Ag2CO3, AgOTf) did also afford coupled
products, albeit in lower yields (1À58%).
ꢀ
J.-M.; De Bo, G.; Marko, I. E. J. Org. Chem. 2008, 73, 4190–4197. (b)
Reference 2a.
3330
Org. Lett., Vol. 14, No. 13, 2012

organosilver intermediate prior to cross-coupling, then
substitution with a triflate should be inconsequential in
the overall process, presuming the PdÀOTf intermediate
is competent in cross-coupling.16À18 As illustrated in
Scheme 4, Hiyama couplings with phenyl triflate were
ineffective.19 We believe this strongly suggests that the
tempered ionization of the PdÀX bond is a key attribute
toward reactivity in these systems.
Table 3. Hiyama Couplings Based on R-Silylenoates 9À11
Scheme 5. Alkenyl Iodide Coupling/Cycloaddition
a Isolated yield. b Reaction temperature: 100 °C.
Finally, these Hiyama couplings can be useful reactions
insyntheticsequencestowardbuildingmolecularcomplex-
ity. An example is depicted in Scheme 5. The coupling of
R-silylenoate 4 and vinyl iodide worked efficiently to
afford diene 20, which was immediately subjected to a
DielsÀAlder reaction with maleic anhydride. Despite the
electron-withdrawing group on the diene moiety, the
cycloaddition proceeded cleanly and effectively at room
temperature to afford tricycle 22. These types of transfor-
mations illustrate the utility these Hiyama couplings may
have in complex molecule synthesis.
Scheme 4. Attempted Hiyama Coupling with Aryl Triflate
Insummary, wehave describedthe selective and efficient
Hiyama couplings of R-silyl electron-deficient alkenes.
Under carefully controlled conditions and employing the
appropriate silicon species, alkene products can be ob-
tained in good yields and with high geometrical integrity.
The application of our efforts in the platinum-catalyzed
hydrosilylations of internal alkynes allows for direct entry
intothese cross-coupling partners. Weanticipate, given the
facile nature of these processes, that this transformation
will be of high value to the synthetic community.
As a first level analysis, we decided to assess the compe-
tency of aryl triflate electrophiles in these cross-couplings.
If the sole role of the silver base is to generate an
(15) Alternative explanations that have been previously proposed but
we do not believe are applicable here are that (1) Ag2O adds as an
activator to make a silicate species to enable transmetalation (ref 13a)
and (2) a tridentate mode of coordination that initiates a Si to Ag
transmetalation (ref 13c).
(16) Although Hiyama couplings with triflates are less prevalent,
there are a number of cases where efficient coupling has been observed.
For select examples, see: (a) Hosomi, A.; Kohra, S.; Tominaga, Y.
Chem. Pharm. Bull. 1988, 36, 4622–4625. (b) Hatanaka, Y.; Hiyama, T.
Tetrahedron Lett. 1990, 31, 2719–2722. (c) Denmark, S. E.; Sweis, R. F.
Org. Lett. 2002, 4, 3771–3774. (d) Riggleman, S.; DeShong, P. J. Org.
Chem. 2003, 68, 8106–8109. (e) Seganish, W. M.; DeShong, P. J. Org.
Chem. 2004, 69, 1137–1143.
Acknowledgment. Colorado State University is ac-
knowledged for support of our program. Eli Lilly is grate-
fully acknowledged for a graduate research fellowship to
D.A.R.
(17) Alkynylsilver species, either isolated or generated in situ, have
been coupled to triflates under palladium catalysis. For examples, see:
(a) Dillinger, S.; Bertus, P.; Pale, P. Org. Lett. 2001, 3, 1661–1664. (b)
Halbes, U.; Pale, P. Tetrahedron Lett. 2002, 43, 2039–2042.
(18) Arylsilicon species based on the (2-hydroxymethyl)phenyl group
have been coupled to aryl imidazol-1-ylsulfonates. See ref 7b.
(19) A number of parameter variations on these optimal conditions
were also evaluated, but ester 6a was never produced.
Supporting Information Available. Experimental pro-
cedures, compound characterization data, and spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
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