Enol silyl ethers via copper(II)-catalyzed C-O bond formation

Article abstract of DOI:10.1021/ol2009297

Copper(II) acetate catalyzes the coupling of pinacol vinylboronates with silanols producing enol silyl ethers. This represents a novel enol silyl ether synthesis via formation of the C-O bond instead of the conventional Si-O bond. This also constitutes the first transition-metal-catalyzed oxidative cross-coupling with silanols.

Full text of DOI:10.1021/ol2009297

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2778–2781
Enol Silyl Ethers via Copper(II)-Catalyzed
CÀO Bond Formation
Daniel G. Chan, David J. Winternheimer, and Craig A. Merlic*
Department of Chemistry and Biochemistry, University of California, Los Angeles,
California 90095-1569, United States
merlic@chem.ucla.edu
Received April 8, 2011
ABSTRACT
Copper(II) acetate catalyzes the coupling of pinacol vinylboronates with silanols producing enol silyl ethers. This represents a novel enol silyl
ether synthesis via formation of the CÀO bond instead of the conventional SiÀO bond. This also constitutes the first transition-metal-catalyzed
oxidative cross-coupling with silanols.
Enol silyl ethers are exceptionally important intermedi-
ates in organic synthesis functioning as latent enolates or
reactive electron rich alkenes. Enol silyl ethers are utilized
in many prominent organic transformations such as Mu-
kaiyama aldol reactions,1 Michael reactions,2 DielsÀAlder
reactions,3 Rubottom oxidations,4 and Saegusa oxida-
tions.5 The vast majority of enol silyl ethers are generated
via O-silylation of carbonyl derivatives using an electro-
philic silicon source (Figure 1).6 Typically, this involves
silylation of preformed enolates or addition of potent
silylating agents to neutral carbonyl derivatives in the
presence of a weak base. These approaches can be proble-
matic in controlling chemoselectivity and the regio- and
stereochemistry of the resultant enol silyl ether. We envi-
sioned a novel synthesis of enol silyl ethers wherein the
CÀO bond is formed instead of the SiÀO bond by employ-
ing cross coupling of a vinyl derivative with a silanol
(Figure 1). We reported a stereospecific copper(II)-pro-
moted coupling of aliphatic and allylic alcohols with
vinylboronates as a facile method by which to synthesize
vinyl ethers.7 This advanced the work originally published
(1) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 2,
1011. (b) Mukaiyama, T. Org. React. 1982, 28, 203. For examples, see:
(c) Panek, J. S.; Jain, N. F. J. Org. Chem. 2001, 66, 2747. (d) Kobayashi,
S.; Furuta, T.; Hayashi, T.; Nishijima, M.; Hanada, K. J. Am. Chem.
Soc. 1998, 120, 908.
(2) (a) Narasaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974,
1223. (b) Oare, D. A.; Heathcock, C. A. Top. Stereochem. 1991, 20, 124.
For examples, see: (c) Wang, W.; Li, H.; Wang, J. Org. Lett. 2005, 7,
1637. (d) Saraber, F. C. E.; Dratch, S.; Bosselaar, G.; Jansen, B. J. M.; de
Groot, A. Tetrahedron 2006, 62, 1717.
(3) For examples, see: (a) Josephsohn, N. S.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4018. (b) Han, G.;
LaPorte, M. G.; Folmer, J. J.; Werner, K. M.; Weinreb, S. M. J. Org.
Chem. 2000, 65, 6293.
(4) (a) Rubottom, G. M.; Vazques, M. A.; Pelegrina, D. R. Tetra-
hedron Lett. 1974, 4319. (b) Hassner, A.; Reuss, R. H.; Pinnick, H. W.
J. Org. Chem. 1975, 40, 3427.
(5) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
For examples, see: (b) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki,
M. J. Am. Chem. Soc. 2002, 124, 14983. (c) Barrett, A. G. M.; Blaney, F.;
Campbell, A. D.; Hamprecht, D.; Meyer, T.; White, A. J. P.; Witty, D.;
Williams, D. J. J. Org. Chem. 2002, 67, 2735.
Figure 1. Approaches to enol silyl ether synthesis.
(6) (a) Brownridge, P. Synthesis 1983, 1. (b) Brownridge, P. Synthesis
1983, 85.
(7) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am.
Chem. Soc. 2010, 132, 1202.
r
10.1021/ol2009297
Published on Web 04/21/2011
2011 American Chemical Society

by Chan, Lam, and Evans8 now known as ChanÀLam
couplings wherein two nucleophiles are oxidatively cou-
pled (modern Ullmann).9 Herein, we report a copper-
catalyzed coupling with silanols to synthesize enol silyl
ethers. This is, to the best of our knowledge, the first report
of transition-metal-catalyzed oxidative couplings using
silanols.
Table 2. Silanol Coupling Optimization
Cu(OAc)2
yield
(%)
entry
(equiv)
change
Table 1. Silanol Cross-Coupling Screening
1
2
2
52
40
36
32
63
32
62
2
without 3-hexyne
3
2
12 equiv of TBS-OH, DCM
2 equiv of NaH
4
2
5
3
N/A
6
3
1 atm of O2
entry
R3Si
TMS
yield (%)
7
0.5
0.5
0.5
0.5
2 equiv of PNO, 1 atm of O2
8
2 equiv of PNO, 1 atm of O2, mol sieves 45
2 equiv of PNO, 1 atm of O2, 14 d 57
1
2
3
4
5
0
47
52
26
0
9
TES
10
2 equiv of PNO, 1 atm of O2, 8 equiv of 42
Et3N
TBDMS
TIPS
11
12
13
1.0
1 equiv of PNO, 1 atm of O2
1 equiv of PNO, 1 atm of O2
1 equiv of PNO, 1 atm of O2
62
31
72
DMPS
0.25
0.5
To explore a cross-coupling synthesis of enol silyl ethers,
vinylboronate 1 was coupled with several silanols using
stoichiometric copper conditions that employ 3-hexyne as
a ligand for copper (Table 1).10 No desired product could
beisolated whenusing trimethylsilanol (entry 1). However,
a 20% yield of 4-benzoxybutanal was obtained indicating
that the product was synthesized, but desilylation of the
product occurred during purification. Triethylsilanol and
tert-butyldimethylsilanol coupled to give silyl enol ethers
with similar efficiencies (47% and 52%, respectively;
entries 2 and 3). The more sterically inhibited triisopro-
pylsilanol coupled in a mere 26% yield and dimethylphe-
nylsilanol failed to provide any coupled product (entries 4
and 5).
With tert-butyldimethylsilanol chosen as the best cou-
pling partner, a variety of conditions were screened in
order to find the optimal protocol (Table 2). In accord with
our report on dienyl ether synthesis,10 we found that added
3-hexyne ligand was critical (entries 1 vs 2) for obtaining
the best yield. Neat silanol was preferred (entry 3), and
attempts to make the silanol more nucleophilic via gen-
eration of the silyloxide with sodium hydride decreased
yields (entry 4). Using 3 equiv of Cu(OAc)2 improved the
yield to 63% (entry 5), and using an oxygen atmosphere
was disadvantageouswith excesscopper (entry 6). Muchto
our delight, catalytic conditions fared as well as using
excess Cu(OAc)2 (entries 7 vs 5).
After our initial report on couplings with alcohols,7 we
optimized a catalytic protocol for vinyl, but not dienyl,
ethers. Systematic examination of the reaction components by
running parallel reactions with changes of single components
revealed that both triethylamine and 3-hexyne ligand were
essential for operation of this catalytic protocol (Table 3,
entries 2 and 3). Additionally, both pyridine N-oxide (PNO)
and oxygen were required oxidants in order to achieve
catalysis (entries 4 and 5). Pyridine N-oxide was chosen as
the oxidant based on observations made by the Lam
group.11 Lastly, using 20 mol % of Cu(OAc)2 resulted in
a drastic decrease in yield (entry 6), indicating that 50 mol %
was the necessary catalyst loading.
Returning to entry 7 employing catalytic conditions in
1
the silanol couplings of Table 2, H NMR analysis of a
sample of 2 prior to purification on silica gel found 20%
aldehyde derived from product hydrolysis and 10% alkene
derivedfromprotodeborationpresent. Thatsuggested that
hydrolysis was occurring in the reaction mixture. Spec-
ulating that water might be responsible, molecular sieves
were added, but without improvement (entry 8). Testing
product stability under the reaction conditions by leaving a
reaction run for 14 days did not lower the yield signifi-
cantly (entry 9). Attempting to reduce protodeboration by
adding more triethylamine was not beneficial either
(entry 10). Using stoichiometric copper acetate did not
improve the yield (entry 11), and lowering to only 25 mol
% reduced the yield (entry 12) in accordance with the
alcohol screening results (Table 3, entry 6). Finally, redu-
cing the amount of pyridine N-oxide (PNO) to1 equiv gave
the best yield (entry 13).
(8) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters,
M. P.; Chan, D. M. T. Tetrahedron Lett. 1998, 39, 2941. (c) Chan,
D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett.
1998, 39, 2933.
(9) For reviews, see: (a) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829.
(b) Chan, D. M. T.; Lam, P. Y. S. In Boronic Acids; Hall, D. G., Ed.;
Wiley-VCH: Weinheim, 2005; Chapter 5. (c) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400.
(11) Clark, C. American Chemical Society Meeting, Boston, MA, Aug
19À23, 2007; American Chemical Society: Washington, DC, 2007.
(10) Winternheimer, D. J.; Merlic, C. A. Org. Lett. 2010, 12, 2508.
Org. Lett., Vol. 13, No. 10, 2011
2779

Table 3. Probing Catalytic Conditions for Alcohol Couplings by
Deleting Components
Table 4. Silyl Enol Ether Synthesis
entry
change
yield (%)
1
2
3
4
5
6
none
95
66
29
18
14
19
delete Et3N
delete 3-hexyne
delete O2
delete PNO
0.3 equiv of Cu(OAc)2
The optimized coupling conditions were then applied to
cross couplings of vinylboronates with tert-butyldimethyl-
silanol to make enol silyl ethers (Table 4). A number of these
examples are quite remarkable as the products would not be
accessible via direct silylation of carbonyl substrates. While
no aldehyde silylation protocol is available that is comple-
tely stereoselective for an E or Z product, entries 1 and 2
prove that the cross coupling reaction is stereospecific. The
modest yield in entry 2 is in line with a low yield obtained in
coupling an alcohol with a pinacol Z-vinylboronate.7 En-
tries 4 and 5 prepare very acid-labile dienyl silyl ether targets.
Entry 6 is formally the enol silyl ether of an aldehy-
deÀalcohol. Entry 8 is the mono enol silyl ether of a
ketoaldehyde, while entry 9 is the mono enol silyl ether of
an aldehydeÀamide. Entries 10 and 11 illustrate access to
base-sensitive targets. Finally, entry 12 presents another
exceptionally acid-labile enol silyl ether. Most of these
examples would be quite challenging to prepare by direct
silylation using either preformed enolates or highly electro-
philic silylating agents in the presence of weak bases.
As a final capstone example, we tested the coupling of
vinylboronate 15 containing both alcohol and ketone
functional groups (Scheme 1). Direct silylation of a hydro-
xy ketoaldehyde would not be feasible using conventional
methods, but silanol coupling with hydroxy ketoboronate
ester 15 provided the target 16 in a reasonable yield. As
with entry 6 in Table 4, no evidence for coupling with the
alcohol was detected.
This methodology is also applicable to aryl substrates as
demonstrated by the coupling of phenylboronic acid and
pinacol phenylboronate with tert-butyldimethylsilanol to
generate the aryl silyl ether 18 (Scheme 2). These couplings
were considerably slower than the vinyl couplings and
required several days for complete consumption of the
substrates. This is the first synthesis of an aryl silyl ether via
CÀO bond formation in an oxidative cross coupling. In
contrast, alkyl aryl ethers have been synthesized via cross
couplings using both copper12 and palladium.13
While the yields in these couplings are not spectacular,
three aspects are especially noteworthy. First, many of the
products are acid sensitive, yet all were isolated by silica gel
chromatography. Second, yields herein are based on bor-
onate ester, whereas many other reports on copper-based
couplings with heteroatom nucleophiles use an excess of
the boron substrates.8,9 Third, coordination of the bypro-
duct acetoxypinacolborate to the enol silyl ether could lead
to desilylation and the boron enolate via a six-center
transition state.
(12) (a) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381.
(b) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973.
(13) Marcoux, J. F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 10539.
(14) Denmark, S. E.; Ober, M. Adv. Synth. Catal. 2004, 346, 1703.
Org. Lett., Vol. 13, No. 10, 2011
2780

Related to direct silylation of carbonyl compounds, oxida-
tion of vinyl metal compounds to enolates with molecular
oxygen or peroxides followed by silylation of the resultant
enolates with electrophilic silicon reagents has been reported.19
There are a few reports on oxidation of vinyllithium anions
with silyl peroxide to provide enol silyl ethers directly,20 but
that method clearly suffers from chemoselectivity issues.
Our working hypothesis for the reaction mechanism is
that it is analogous to the copper-based couplings with
alcohols7À9 and that a silyloxy vinyl copper(III) intermedi-
ate is key for reductive elimination forming the CÀO bond
and copper(I). Copper(0) is not observed in the reactions,
and a mechanistic rationale for the importance of both
oxygen and pyridine N-oxide is not clear.
Scheme 1. Capstone Coupling Example
In conclusion, we found that silanols can be coupled with
vinylboronate esters using catalytic Cu(OAc)2 as a facile,
chemoselective, and stereospecific method to synthesize enol
silyl ethers. This represents a novel synthesis of silyl ethers as
it involves CÀO instead of SiÀO bond formation. Use of 0.5
equiv of Cu(OAc)2 with both pyridine N-oxide and oxygen
as oxidants was found to be optimal for these couplings.
These catalytic conditions were effective for synthesis of a
variety of enol silyl ethers containing functional groups that
would be problematic or impossible using typical carbonyl
silylation conditions for SiÀO bond formation.
Scheme 2. Phenyl Couplings
CÀO bond formation via cross coupling with silanols is
not an obvious choice since aryl,14 alkenyl,15 and alkynyl16
silanols have been demonstrated to deliver the carbon
substituent in cross couplings and that reactivity is used
beneficially in complex molecule total synthesis.17 Indeed, in
the reaction employing dimethylphenylsilanol (Table 1, en-
try 5), no silyl enol ether or aldehyde was detected, but a
small amount (<10%) of phenyl coupling was detected by
mass spectrometry. tert-Butyldimethylsilanol has been uti-
lized in a typical metal(0)-catalyzed cross coupling with aryl
bromides,18 but the analogous reaction with alkenyl halides
has not been reported. Furthermore, aryl or vinyl oxidative
cross couplings using silanols has not been reported.
Acknowledgment. We are grateful to the National
Science Foundation and the Research Corporation for
Science Advancement for financial support.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds, includ-
1
ing scanned images of H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) (a) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F.
J. Org. Chem. 2002, 67, 5553. (b) Shelby, Q.; Kataoka, N.; Mann, G.;
Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 10718. (c) Mann, G.;
Hartwig, J. F. J. Org. Chem. 1997, 62, 5413.
(19) (a) DeBergh, J. R.; Spivey, K. M.; Ready, J. M. J. Am. Chem. Soc.
2008, 130, 7828. (b) Zhang, D.; Ready, J. M. Org. Lett. 2005, 7, 5681.
(20) (a) Davis, F. A.; Lal, G. S.; Wei, J. Tetrahedron Lett. 1988, 29,
4269. (b) Neuman, H.; Seebach, D. Chem. Ber. 1978, 111, 2785.
(15) (a) Denmark, S. E.; Sweis, R.; Wehrli, D. J. Am. Chem. Soc.
2004, 126, 4865. (b) Denmark, S. E.; Sweis, R. Org. Lett. 2002, 4, 3771.
(16) Chang, S.; Yang, S. H.; Lee, P. H. Tetrahedron Lett. 2001, 42,
4833.
(17) Denmark, S. E.;Liu, J. H.-C. Angew. Chem., Int. Ed. 2010, 49, 2978.
Org. Lett., Vol. 13, No. 10, 2011
2781