Copper-catalyzed addition of nucleophilic silicon to aldehydes

Article abstract of DOI:10.1002/anie.201209020

How to train your silane: A new family of chiral copper(I) complexes that bear a bifluoride counteranion were prepared and used in the first example of the enantioselective transfer of a silyl group to an aldehyde. This procedure provides fast access to non-racemic α-hydroxysilanes in high enantioselectivities. Copyright

Full text of DOI:10.1002/anie.201209020

Angewandte
Chemie
DOI: 10.1002/anie.201209020
Enantioselective Silylation
Copper-Catalyzed Addition Of Nucleophilic Silicon To Aldehydes**
Virginie Cirriez, Corentin Rasson, Thomas Hermant, Julien Petrignet, Jesffls Díaz lvarez,
Koen Robeyns, and Olivier Riant*
The transition metal-catalyzed transfer of silicon nucleo-
philes[1] onto various electrophiles, has recently gained
considerable attention,[2] owing to the development of readily
available silicon pro-nucleophiles. In particular, the reagent
but the use of such strongly basic nucleophiles is not without
problems for functionalized aldehydes.
Recently, Oestreich described the racemic 1,2-addition of
a silicon nucleophile to imines and aldehydes, and proposed
À
À
developed by the Suginome group, which possesses a Si B
a mechanism involving a Cu Si intermediate as the silyl
linkage has become one of the major sources of nucleophilic
silicon.[1a] This new method is particularly attractive, as it
provides a facile access to metal–silicon reagents that render
the use of any activating agents unnecessary.
transfer species.[2d,15] The mild copper-mediated generation of
À
nucleophilic silicon from Si B compounds might therefore be
useful for catalytic one-step access to enantiomerically pure
a-hydroxysilanes from readily available aldehydes.
These metal–silicon intermediates allow the catalytic
transfer of a silicon nucleophile onto various electrophiles;
our interest lies in the addition of such species to aldehydes,
Herein, we report the first enantiomeric version of the 1,2-
addition of a silicon nucleophile to aromatic and aliphatic
aldehydes catalyzed by copper(I) complexes.
À
thus generating a-hydroxysilanes. This type of C Si bond
Our investigation started with benzaldehyde, which was
selected as a model substrate for initial screening. The
formation as well as the hydroxy group is of crucial
importance in organic synthesis. Moreover, a stereogenic
center is formed in this process, thus generating possible
opportunities for asymmetric catalysis.
= À
reaction of 1a with Me2PhSiBpin (2; Si B, pin = pinaco-
lato)[16] in the presence of CuF(PPh3)3·2 MeOH (3)[17] as the
copper catalyst was completed in 2 h at room temperature,
and resulted in the isolation of racemic a-hydroxysilane in
39% yield. To establish suitable reaction conditions, we first
optimized the reaction temperature and solvent. We obtained
the best results by running the reaction in THF at room
temperature. We then screened different catalysts and
additives, as shown in Table 1.
Optically active a-hydroxysilanes are a class of chiral
organometallic compounds that contain a functional group.
These molecules and their derivatives have been used for
À
stereocontrolled C C bond formation and rearrangements,
which resulted in a wide variety of chiral organic com-
pounds.[3–7] The majority of literature-known methods for the
preparation of a-hydroxysilanes are based on the asymmetric
reduction of acylsilanes[8] or the hydrogenation of enol-
silanes.[9] However, the synthesis of acylsilanes usually
requires several steps.[10] An alternative, but less used,
approach is the one previously described, which includes
the addition of a silicon nucleophile to a carbonyl com-
Table 1: Selected experiments from the optimization of the copper-
catalyzed 1,2-addition reaction of nucleophilic silicon to aldehyde 1a.
pound.[11–14] Hiyama et al. introduced a fluoride-catalyzed Si
À
Si bond cleavage followed by the addition of released silicon
nucleophiles to aldehydes.[11] However, yields were partially
diminished by [1,2]-Brook rearrangement. Barrett and Hill[13]
elaborated a practical procedure based on the addition of
easy-to-form Me2PhSiLi to aliphatic and aromatic aldehydes,
Entry
[Cu] (5 mol%)
L (10 mol%)
Yield [%][a]
ee [%][b]
1
2
3
4
3
3
3
–
39[c]
37
49
0
12
23
46
–
–
5
(rac)-binap
5
5
6
7
7
CuCl/NaOtBu
CuCl/NaOtBu
CuCl/NaOtBu
CuCl/NaOtBu
–
5
20
84
97
6
[*] V. Cirriez, C. Rasson, T. Hermant, Dr. J. Petrignet, Dr. J. Dꢀaz ꢁlvarez,
Dr. K. Robeyns, Prof. O. Riant
7[d]
[a] Yield of isolated product after hydrolysis and flash chromatography
on silica gel. [b] Determined by HPLC analysis on a chiral stationary
phase. [c] Conversion was complete in 2 h. [d] MeOH (4 equiv) was used
as an additive.
Institute of Condensed Matter and Nanosciences, Molecules, Solids
and Reactivity (IMCN/MOST)—Universitꢂ Catholique de Louvain
Place Louis Pasteur 1, bte L4.01.02
1348 Louvain-la-Neuve (Belgium)
E-mail: olivier.riant@uclouvain.be
[**] Financial support from the Universitꢂ Catholique de Louvain is
gratefully acknowledged. Takasago International is gratefully
acknowledged for a generous gift of Segphos ligands. Laurent
Collard is gratefully acknowledged for his work on the separation of
chiral products.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209020.
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We found that diphosphine ligands, (rac)-2,2’-bis(diphe-
nylphosphino)-1,1’-binaphthyl (binap) and MeO-biphep (5;
see Table 1 for structure), when used with 3 also promoted the
1,2-addition, but a prolonged reaction time was required
(Table 1, entries 2 and 3). Moreover, no significant enantio-
selectivity was observed with chiral ligands, because the
reaction was much faster with PPh3 as the ligand (Table 1,
entry 3). Therefore, we decided to change the catalytic
system. When diphosphine 5 was used in combination with
the CuCl/NaOtBu system, the reaction did not give the
desired product 4a (Table 1, entry 4). When we used the P–N
ligand 6, a 12% yield was obtained, but we observed a modest
increase in enantioselectivity up to 20%. The use of the
sterically hindered ligand DTBM-Segphos (7) considerably
improved the enantioselectivity (Table 1, entry 6). Finally, the
addition of methanol led to significant improvement of both
the yield and enantioselectivity, which suggests that methanol
plays a significant role in regenerating the catalyst (Table 1,
entry 7). The optimized conditions were found to be: CuCl
(5 mol%), NaOtBu (5 mol%), MeOH (4 equiv), and (R)-
DTBM-Segphos (10 mol%) at room temperature in THF.
The desired product was obtained in 46% yield and 97% ee.
However, we found that these conditions gave fairly irrepro-
ducible results, both for yields and enantioselectivities, with
significant drops (down to 65% from 97%) in the enantio-
selection.
Scheme 1. Synthesis of new diphosphine copper(I) bifluoride com-
plexes.
À139.6 ppm for Cu-F-H-F and d = À192.4 ppm for Cu-F-H-
F). This was confirmed by crystallization in toluene/n-hexane
which afforded crystals of X-ray quality for analysis. The
structure confirmed the formation of a neutral complex
bearing a s-bonded H2F3À anion. Finally, we were delighted to
find that those complexes are very air and moisture stable,
both in the solid state and in solution, and display excellent
reactivity in our model reaction.
Recently, our group developed a new pathway to unpre-
cedented N-heterocyclic carbene (NHC) copper(I) bifluoride
complexes, which proved to be excellent catalysts for
nucleophilic transfer to electrophilic double bonds, aldehydes,
and chiral imines.[19] Furthermore, hydrogen bifluoride
(FHFÀ) is a unique anion, as it features the strongest known
hydrogen bond.[18] This anion is also an anhydrous source of
These new complexes 9a,b were tested in the copper-
catalyzed 1,2-addition of a silicon nucleophile to aldehydes.
Reaction of 1a with 2 and copper complex 9a (5 mol%)
under the previously established optimized conditions, was
completed in 16 h to afford the (R)-a-hydroxysilane (R)-4a in
> 99% ee and 87% yield of isolated product. The use of
copper complex 9b afforded the (S)-a-hydroxysilane (S)-4a
in > 99% ee and 82% yield of isolated product (Table 2,
entries 1 and 2). The absolute configuration of compound 4a
is based on literature data.[8d]
The optimized reaction conditions were then applied to
various aromatic and aliphatic aldehydes 1a–q (Table 2).
Regarding aromatic aldehydes, both electron-donating as well
as electron-withdrawing groups were well tolerated. Yields of
isolated products were good to high and the corresponding a-
hydroxysilanes were obtained with excellent enantioselectiv-
ity. The electronic substitutions on the aromatic ring did not
affect the enantioselectivity. However, aromatic aldehydes
with functional groups at the ortho-position proved to be less
reactive and gave the product in moderate yield (Table 2,
entries 3 and 16), as a consequence of the steric hindrance at
the ortho position. To our delight, we found that aliphatic
aldehydes reacted well (Table 2, entries 9, 12, and 13).
However, propionaldehyde gave the desired product in only
87% ee (Table 2, entry 12). This result suggests that the
aldehyde is not bulky enough to obtain good selectivity.
Neither aromatic aldehydes with reactive functional groups in
the para position (NO2 and OH groups) nor pyridine-4-
carboxaldehyde yielded the desired a-hydroxysilane.
À
fluoride that can activate the Si B reagent 2, thus avoiding
the need for co-catalysts such as alkoxides. These observa-
tions prompted us to design a new family of well-defined
diphosphine copper(I) complexes bearing a bifluoride coun-
teranion, which might lead to better control of the formation
of the copper–nucleophile active species, and thus reprodu-
cible experiments. The original procedure was then modified
and we found that the reaction of copper(I) iodide with
silver(I) hydrogen fluoride in acetonitrile gave, after the
removal of silver iodide by filtration, the tetrakis(acetonitrile)
copper(I) hydrogen bifluoride intermediate (8) in situ. The
complex was identified by a sharp singlet at d = À166 ppm by
19F NMR analysis (in CD3CN) and an acidic proton at d =
1
14.1 ppm by H NMR analysis, but could not be isolated by
crystallization. However, the addition of ligands 7a,b gave,
after removal of the solvent, the new cationic complexes 9a,b
(Scheme 1) in excellent yield. We found that, depending on
the quality of the starting commercial silver bifluoride, the
bifluoride anion could be contaminated with dihydrogen
trifluoride anion (see the Supporting Information for details),
albeit without any detrimental effect on their catalytic
activity. Furthermore, 19F NMR analysis suggested that
those complexes can exist either in cationic form in coordi-
nating solvents such as acetonitrile (one sharp peak around
d = À165.5 ppm) or as neutral copper-fluoride-bound com-
plexes in non-coordinating solvents such as benzene (d =
Finally, we decided to check the reactivity of more
challenging substrates, such as a,b-unsaturated aldehydes,
for which competition between 1,2- and 1,4- addition could be
expected. Citral 10[20] reacted with Me2PhSiBpin in the
2
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argon cycles, then THF (3 mL) was added. After the solids were
Table 2: Substrate scope of the copper-catalyzed 1,2-addition of nucle-
ophilic silicon to aldehydes.
dissolved, freshly distilled aldehyde (0.5 mmol, 1 equiv) was added.
Me2PhSiBpin 2 (1.2 equiv) was then added dropwise. Finally, MeOH
(4 equiv) was added and the mixture was stirred at room temperature
overnight. NaBO3 (4 equiv), Et2O (1 mL) and water (3 mL) were
added, and the mixture stirred for 3 h. Et2O (5 mL) was then added
and the phases separated. The aqueous phase was extracted with Et2O
(3 ꢀ 5 mL). The combined organic phases were then sequentially
washed with sat. aq. NH4Cl (15 mL), sat. aq. NaHCO3 (15 mL), and
brine (15 mL), then dried over MgSO4 and concentrated under
reduced pressure. Finally, the product was purified by flash chroma-
tography on silica gel. For further details, see the Supporting
Information.
Entry Aldehyde
R
Product Yield [%][a] ee [%][b]
1
1a
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
Ph
Ph
(R)-4a
(S)-4a
4b
87
82
51
99
78
53
80
95
67
60
99
60
88
98
99
66
98
65
>99
>99
99
2[c]
3
2-MeC6H4
2-thiophene
4-MeC6H4
4-(MeO)C6H4
3,4-(MeO)C6H4
4-PhC6H4
Cy
1-naphtyl
3-(MeO)C6H4
CH3CH2
Ph(CH2)2
4-(CN)C6H4
3-ClC6H4
2-BrC6H4
4-FC6H4
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4c
4d
4e
>99
96
96
4 f
95
Received: November 11, 2012
Published online: && &&, &&&&
4g
95
4h
4i
>99
96
Keywords: aldehydes · asymmetric catalysis · copper ·
.
4j
96
nucleophilic addition · silicon
4k
87
4l
>99
95
94
4m
4n
4o
À
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93
4p
4q
98
>99
4-CF3C6H4
[a] Yield of isolated product after flash chromatography on silica gel.
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À
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In conclusion, we have reported the first example of the
highly reactive and enantioselective addition of a silicon
nucleophile to aldehydes, catalyzed by newly developed
copper(I) complexes 9a,b. A series of aromatic and aliphatic
aldehydes were converted into the corresponding a-hydroxy-
silanes in excellent ee and good to high yields. Thus, this
method provides a new and practical route to producing chiral
silane compounds from readily available aldehydes. Mecha-
nistic investigations are in progress.
Experimental Section
General procedure for the synthesis of a-hydroxysilane: Copper(I)
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4
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Chemie
Communications
Enantioselective Silylation
V. Cirriez, C. Rasson, T. Hermant,
J. Petrignet, J. Dꢁaz ꢂlvarez, K. Robeyns,
O. Riant*
&&& — &&&
How to train your silane: A new family of
chiral copper(I) complexes that bear
a bifluoride counteranion were prepared
and used in the first example of the
enantioselective transfer of a silyl group
Copper-Catalyzed Addition Of
Nucleophilic Silicon To Aldehydes
to an aldehyde. This procedure provides
fast access to non-racemic a-hydroxysi-
lanes in high enantioselectivities.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!