Tweaking copper hydride (CuH) for synthetic gain. A practical, one-pot conversion of dialkyl ketones to reduced trialkylsilyl ether derivatives

Article abstract of DOI:10.1021/ol035164+

(Matrix presented) Variations in the reagents and stoichiometries used to generate CuH in situ, as well as the nature of the ligands present, have led to a very efficient and inexpensive method for effecting hydrosilylations of dialkyl ketones.

Full text of DOI:10.1021/ol035164+

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3085-3088
Tweaking Copper Hydride (CuH) for
Synthetic Gain. A Practical, One-Pot
Conversion of Dialkyl Ketones to
Reduced Trialkylsilyl Ether Derivatives
Bruce H. Lipshutz,* Christopher C. Caires, Peter Kuipers, and Will Chrisman
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Barbara, California 93106
lipshutz@chem.ucsb.edu
Received June 24, 2003
ABSTRACT
Variations in the reagents and stoichiometries used to generate CuH in situ, as well as the nature of the ligands present, have led to a very
efficient and inexpensive method for effecting hydrosilylations of dialkyl ketones.
Hexameric CuH‚Ph3P1 was introduced by Stryker in 1988
as an excellent reagent for effecting conjugate reductions of
R,â-unsaturated carbonyl compounds.2 Its potential to reduce
both aldehydes and ketones in a 1,2-sense, however, has only
recently become of synthetic value.3 Molecular hydrogen,3a,b
Bu3SnH,3c and various silanes3d,e can serve as stoichiometric
sources of hydride, thereby allowing CuH to be used
catalytically. The latter set of conditions (i.e., CuH‚Ligand/
silane) results in a net carbonyl hydrosilylation, which can
be performed asymmetrically4 in the presence of a nonra-
cemic ligand (e.g., Roche’s 3,5-xyl-MeO-BIPHEP5 or Takasa-
go’s DTBM-SEGPHOS6) in the presence of excess
PMHS at low temperatures.7 Aryl silanes (e.g., PhMe2SiH,
Ph2MeSiH), in addition to PMHS, readily participate in this
process.8 Unfortunately, both Et3SiH (TES-H) and t-BuMe2-
SiH (TBS-H) lead, at best, to traces of the desired alcohol-
derived silyl ethers, even in the case of aldehydes.3e Recently,
Grubb’s catalyst has been shown to activate silanes leading
to hydrosilylations of ketones, although reactions with TES-H
or TBS-H require heating.9
Because TBS is among the most valued of alcohol pro-
tecting groups,10 we have endeavored to elucidate the ex-
perimental parameters that play a role in determining the
extent of participation by a given silane. In this Letter we
describe several new insights regarding the in situ generation
of ligated “CuH”11 and document that by control of stoichi-
(1) Churchill, M. R.; Bezman, S. A.; Osborn, J. A.; Wormald, J. Inorg.
Chem. 1972, 11, 1818. Churchill, M. R.; Bezman, S. A.; Osborn, J. A.;
Wormald, J. J. Am. Chem. Soc. 1971, 93, 2063.
(2) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291. See also: Goeden, G. V.; Caulton, K. G. J. Am. Chem.
Soc. 1981, 103, 7354.
(3) (a) Chen, J.-X.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M.
Tetrahedron 2000, 56, 2153. (b) Chen, J.-X.; Daeuble, J. F.; Stryker, J. M.
Tetrahedron 2000, 56, 2789. (c) Lipshutz, B. H.; Ung, C. S.; Sengupta, S.
Synlett 1989, 64. (d) Brunner, H.; Miehling, W. J. Organomet. Chem. 1984,
275, C17. (e) Lipshutz, B. H.; Chrisman, W.; Noson, K. J. Organomet.
Chem. 2001, 624, 367.
(5) (a) Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricher,
J.; Lalonde, M.; Muller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure
Appl. Chem. 1996, 68, 131. (b) Schmid, R.; Foricher, J.; Cereghetti, M.;
Schonholzer, P. HelV. Chim. Acta 1991, 74, 370.
(6) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(7) Lipshutz, B. H.; Noson, K.; Chrisman, W. J. Am. Chem. Soc. 2001,
123, 12917.
(8) Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower, A. J. Am. Chem.
Soc. 2003, 125, 8779.
(9) Maifeld, S. V.; Miller, R. L.; Daesung, L. Tetrahedron Lett. 2002,
43, 6263.
(4) Nishiyama, H.; Itoh, K. Asymmetric Hydrosilylation and Related
Reactions. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH:
New York, 2000; Chapter 2.
(10) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991. (b) Kocienski, P. J. Protecting
Groups; Thieme: Stuttgart, 1994.
10.1021/ol035164+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/02/2003

ometry a straightforward and effective method has been
uncovered for converting dialkyl ketones to their TES and
TBS ether derivatives at room temperature in high yields.
Previously, we have shown that both Roche’s BIPHEP-
and Takasago’s SEGPHOS-type ligands are exceptional
relative to Ph3P for dramatically accelerating the reducing
capabilities of in situ generated CuH.7,8 An extensive study
was undertaken to determine which mono- and/or bidentate
phosphine ligands would impact the catalytic cycle such that
TES ethers could readily be formed from ketones. Figure 1
Figure 2. Representative hydrosilylations with triethylsilane.
precursor ketones using substrate-to-ligand ratios of 2000:
1. Decreasing the amount of silane from 5 to 1.5 equiv had
essentially no impact on reaction efficiency.
Attempts to apply these conditions using TBS hydride
(t-BuMe2SiH)18 in place of Et3SiH were unsuccessful; with
even greater amounts of copper (up to 5%) and ligand (up
to 0.5%), only limited conversion took place. This encour-
aged us to question the extent of CuH formation both initially
and in the catalytic cycle, since it is possible that the silane
is too bulky to undergo hydride delivery either to [CuO-t-
Bu]n or the initial product of ketone reduction (i.e., a copper
alkoxide 6; Scheme 1).19 We also came to question the
Scheme 1
Figure 1. Effective ligands for the hydrosilylation of ketones with
triethylsilane.
shows several of the latter, which at S/L ratios of 200:1 gave
complete conversion, including BIPHEP 1, SEGPHOS 2,
Me-DuPHOS 3,12 BITIANP 4,13 and o-DPPB 5.14 Other
monodentate (e.g., n-Bu3P) or bidentate ligands (e.g., BINAP,
Josiphos,15 DIOP, and tetramethyl-BITIOP16) led to 0-43%
conversion under otherwise identical conditions.
By lowering the amount of ligand further (to S/L ) 2000:
1), only ligands 1, 2, and 5 led to full consumption of educt.
This single modification in choice of ligand was sufficient,
in the case of Et3SiH,17 to afford products of hydrosilylation
on dialkyl ketones in excellent isolated yields. Figure 2
illustrates representative TES ethers formed from their
original prescription for generating CuH,2 that is, what is
the effect of changing the base to something other than tert-
butoxide? With no guidance on this issue from the literature,
commercially available, NaHMDS (0.6 M in toluene) was
tested in combination with CuCl using benzylacetone (7) as
educt (Scheme 2).
Although the standard ratio (1:1 CuCl:base) led to 50%
conversion, increasing the amount of NaHMDS to 2 equiv
relative to copper drove the reaction to 96% completion. The
switch to a nitrogenous base was predicated on the potential
for added stabilization of copper by the amine and the well-
(11) For an alternative set of conditions for generating and using CuH,
see: Sirol, S.; Courmarcel, J.; Mostefai, N.; Riant, O. Org. Lett. 2001, 3,
4111.
(12) Burk, M. J.; Feaster, J. E.; Nugent, W. A.;Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125.
(13) Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.; Antognazza,
P.; Cesarotti, E.; Demartin, F.; Pilati, T. J. Org. Chem. 1996, 61, 6244.
(14) Commercially available from Aldrich, catalog no. 46, 027-3.
(15) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062.
(16) Benincori, T.; Cesarotti, E.; Piccolo, O.; Sannicolo, F. J. Org. Chem.
2000, 65, 2043.
(17) Triethylsilane was obtained from Aldrich in a SureSeal bottle and
used as received.
(18) TBS-H was purchased from Gelest and distilled prior to use.
(19) Chiu, P.;Li, Z.; Fung, K. C. M. Tetrahedron Lett. 2002, 44, 455.
3086
Org. Lett., Vol. 5, No. 17, 2003

Scheme 2
Figure 3. Representative hydrosilylations with TBS-H.
bisphosphine 514 can be used in this context as long as the
known activating and transition state stabilizing effect of
silicon â to copper.20
1:6 ratio of CuCl to base is maintained (eq 4).
In returning to NaO-t-Bu as base, however, with higher
ratios vs CuCl, dramatic improvements were also observed,
suggesting that the ratio of Cu(I) to base, rather than the
nature of the base, is a key parameter. Ultimately, by
lowering the percentage of CuCl (from 3% to 0.5%) while
maintaining the level of base (NaO-t-Bu) at 3%, an es-
sentially complete reaction was realized in only a few hours
at ambient temperature (eq 1). Moreover, only 1.2 equiv of
TBS silane were required, with the S/L ratio at 1000:1 (using
DM-SEGPHOS, 2). Solvents in which essentially identical
rates were observed included toluene, ether, and methylene
chloride. As expected, neither LiO-t-Bu or LiN(TMS)2 in
place of their sodio analogues led to an active reagent.21
The impact of microwave irradiation on the rates of
hydrosilylation of dialkyl ketones (cf. eq 4) was briefly
examined. Conversions could be dramatically reduced to <15
min independent of whether reactions were run in solution
or neat (Figure 4).
Figure 4. Representative hydrosilylations with microwave irradia-
tion (isolated yields).
Even more remarkable was the observation that NaO-t-
Bu could readily be replaced by commercial NaOMe. Using
the same 1:6 ratio of CuCl to now NaOMe, without change
of solvent (1.5 M, including the volume of silane) or S/L
ratio (1000:1), complete conversion could be achieved in less
than 3 h (eq 2). The amount of CuCl could also be reduced
to 0.1% without impact.
Attempts to apply these conventional solution conditions
to the one-pot conversion of an aldehyde (e.g., hydrocinna-
maldehyde) to the corresponding TBS-protected primary
alcohol were completely unsuccessful; less than 10% yields
were realized, along with considerable byproduct formation
in large measure due to competing aldol-based events (eq
5). Likewise, asymmetric hydrosilylation of aryl ketone7,8
8
to afford a nonracemic secondary silyl ether could not be
achieved at sufficiently low temperatures so as to maximize
both conversion and ee; at g -7 °C the ee was only 80%
(eq 6).
Two additional examples run under these newly developed
conditions on precursor ketones, which led to high isolated
yields of reduced silyl ethers, are highlighted in Figure 3.
These conditions (using NaO-t-Bu) were also directly
applicable to TES ether formation (eq 3).
In summary, a simple protocol has been developed for
effecting the single-flask conversion of dialkyl ketones to
Although these powerful ligands (15 and 26) are likely to
be used extensively and hence become more accessible in
the future, we have found that commercially available
(20) (a) Eaborn, C. J. Organomet. Chem. 1975, 100, 43. (b) Eaborn, C.
J. Chem. Soc., Chem. Commun. 1972, 1255. (c) Bertz, S. H.; Eriksson, M.;
Miao, G.; Snyder, J. P. J. Am. Chem. Soc. 1996, 118, 10906.
Org. Lett., Vol. 5, No. 17, 2003
3087

their corresponding TES and TBS ethers based on an in situ
generated, catalytic hydrido copper complex.22 This method
is competitive with the conventional two-pot approach
involving metal hydride reduction followed by silyl halide/
triflate protection. The unprecedented impact of the stoichi-
ometry of base present on both the reactivity and stability
of the reagent, along with the significant benefits of selected
bidentate phosphine ligands, introduce new subtleties so often
associated with organocopper chemistry.24
to Dr. Takao Saito and Mr. Hideo Shimizu (Takasago), Drs.
R. Schmid and M. Scalone (Hoffmann-La Roche), and Prof.
Sannicolo (University of Milan), for their generosity in
providing the biaryl ligands used in this study. Discussions
with, and comments by, Prof. Jeffrey Stryker (University of
Alberta, Edmonton) are greatly appreciated.
Supporting Information Available: Complete spectro-
scopic data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial suppport provided by the
NSF is warmly acknowledged with thanks. We are indebted
OL035164+
(21) Brestensky, D. M.; Huseland, D. E.; McGettigan, C.; Stryker, J.
M. Tetrahedron Lett. 1988, 29, 3749.
TLC. Upon completion (3 h) the mixture was exposed to air for 20 min
and then filtered through a pad of Celite and activated charcoal. The filter
cake was washed three times with 10 mL of hexanes. The filtrate was
concentrated in vacuo to afford 1.57 g (99%) of the known23 product as a
colorless oil.
(23) Pilcher, A. S.; DeShong, P. S. J. Org. Chem. 1993, 58, 5130.
(24) Individual control experiments designed to test the requirement for
CuCl, base, and the ligand were conducted. In all cases, whether under
conventional or microwave conditions, all three components were essential
for hydrosilylation to occur.
(22) Representative Procedure for the Preparation of TBS Ethers
from Ketones. An oven-dried 10-mL round-bottomed flask (RBF) was
equipped with a magnetic stir bar and purged with argon. Cu(I)Cl (3.0 mg,
0.03 mmol), NaOMe (9.7 mg, 0.18 mmol), and DM-SEGPHOS (5.1 mg,
0.006 mmol) were added as solids and stirred in diethyl ether (2.8 mL, 1.5
M) for 20 min. The RBF was then charged with tert-butyldimethylsilane
(1.2 mL, 7.2 mmol, 1.2 equiv) followed by benzylacetone (0.9 mL, 6.0
mmol). The reaction was stirred at room temperature and monitored by
3088
Org. Lett., Vol. 5, No. 17, 2003