1-Hydrosilatrane: A Locomotive for Efficient Ketone Reductions

Article abstract of DOI:10.1002/ejoc.201601256

An efficient method for the reduction of ketones with 1-hydrosilatrane is described. In the presence of a Lewis base activator, the resulting secondary alcohols are rapidly formed in good to excellent yields (20 examples, 71–99 % yields). The relative bulkiness of 1-hydrosilatrane also enables the diastereoselective reduction of (–)-menthone to (+)-neomenthol, and the use of a chiral alkoxide activator can lead to the enantioselective reduction of prochiral ketones.

Full text of DOI:10.1002/ejoc.201601256

A Journal of
Accepted Article
Title: 1-Hydrosilatrane: a locomotive for efficient ketone reductions
Authors: Sami E Varjosaari; Vladislav Skrypai; Paolo Suating; Joseph J.M. Hurley;
Thomas M. Gilbert; Marc J. Adler
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601256
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601256
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COMMUNICATION
1-Hydrosilatrane: a locomotive for efficient ketone reductions
Sami E. Varjosaari,[a] Vladislav Skrypai,[a] Paolo Suating,[a] Joseph J. M. Hurley,[a] Thomas M. Gilbert,[a]
and Marc J. Adler*[a]
Abstract: An efficient method for the reduction of ketones with 1-
hydrosilatrane is described. In the presence of a Lewis base
activator, resulting secondary alcohols are rapidly formed in good to
excellent yields (20 examples, 71-99% yields). The relative bulkiness
of 1-hydrosilatrane also allows for diastereoselective reduction of (-)-
menthone to (+)-neomenthol, and use of a chiral alkoxide activator
can lead to the enantioselective reduction of prochiral ketones.
stability with respect to other silanes.15 It is air and moisture
stable, easy to handle, and cheaply synthesized from
boratrane.15b
The reduction of carbonyl groups is one of the most significant
and well-studied chemical transformations, providing access to a
plethora of products from simple starting materials.1 The
development of chiral reducing agents has further given access
to asymmetric products,1a including the crucially important
optically pure secondary alcohols, from prochiral ketones.2
Organosilicon hydrides, simply referred to as silanes, can
act as hydride sources in such reduction reactions. Unlike
borohydrides and aluminohydrides, however, silanes are
typically weak hydride donors and thus do not react with weak
electrophiles such as ketones and aldehydes unless the
electrophilicity of the carbon center is enhanced.3 Such
activation can be achieved by adding a Lewis acid, which can
coordinate with the carbonyl oxygen;4 alternatively, the Lewis
acid can activate the silicon hydride bond, making the hydride
much more nucleophilic.5 In a related approach, the silicon itself
can be made more Lewis acidic by adding a Lewis base whose
affinity for silicon is high, such as a fluoride,6 or an oxide anion:7
this results in a Lewis acidic hypervalent pentacoordinate
hydrosilanide anion, which can form a complex with the carbonyl
oxygen and then donate its hydride to the electrophilic carbon
center. The increased hydride donating ability of hypervalent
silicon is well known8 and has been studied and exploited in an
array of chemical transformations.9
Figure 1. 1-Hydrosilatrane.
Although 1-arylsilatranes are known to be toxic,16 having
been commercialized as zooicides17 and even being portrayed
as poison in movies,18 1-hydrosilatrane has a much better safety
profile: the hydride derivative possesses an intraperitoneal (IP)
LD50 of 100 mg/kg while the dangerous aryl-substituted version
has an IP LD50 of 0.33 mg/kg.19 Interestingly, 1-alkyl and 1-
alkoxysilatranes (with IP LD50s of 3000 and 2100 mg/kg,
respectively) are non-toxic16a and actually have pharmacological
properties20 and beneficial effects when fed to livestock.21
The application of 1-hydrosilatrane (1) as a reducing agent
was published in 1976 by Eaborn et al., who reported the
reduction of both acetone and 4-hydroxybenzaldehyde without
an activator.22 This work was narrow in scope, and furthermore
irreproducible in our hands. We were inspired, however, and
proceeded to develop a method for the reduction of aldehydes
using 1 in the presence of a Lewis base activator.23 Herein we
discuss the activation of 1-hydrosilatrane (1) with a Lewis base
to reduce ketones in an operationally simple manner, as well as
scope and stereoselectivity of the reaction.
Acetophenone
(2a)
was
reduced
in
N,N-
Currently polymethylhydrosiloxane (PMHS) is the most
commonly used silane for carbonyl reduction due to its low
toxicity, relatively high stability, and low cost.10 Mechanistic
studies have suggested that it forms the volatile and dangerous
MeSiH3 in situ as the active reducing species.7e A similar
disproportionation is known to occur with (EtO)3SiH, which forms
the extremely pyrophoric SiH4.11 These unwanted attributes
could create complications for large scale industrial applications.
Silatranes are caged structures in which the nitrogen atom
donates its lone pair of electrons to the silicon, forming a
pentacoordinate silicon.12 Since their discovery in the 1960s,13
they have been extensively studied for myriad uses.14 1-
Hydrosilatrane (Figure 1) is a promising reducing agent due to
its pre-activated pentacoordinate silicon atom and relatively high
dimethylformamide (DMF) at room temperature within 70
minutes using 1.1 equivalents of 1-hydrosilatrane in the
presence of 1 equivalent of potassium tert-butoxide, giving 94%
conversion to 1-phenylethanol (3a) (Table 1, Entry 1). A brief
survey of solvents (Table 1, Entries 2-4) suggested that the
more polar the solvent, the greater the yield of alcohol from
ketone: this is likely due to the fact that 1 is more soluble in polar
solvents.
Substitution of sodium hydroxide for tert-butoxide (Table 1,
Entry 5) induced reduction of acetophenone (2a), but with low
conversion. Excess amounts of sodium hydroxide in optimized
conditions gave higher yields, but these still were not as good as
with tert-butoxide (see Supporting Information). Milder Lewis
bases (Table 1, Entries 6-7) gave no conversion, indicating the
need of a stronger base to activate 1. Lowering the amount of
tert-butoxide to 0.5 equivalents gave lower yields (Table 1, Entry
8). However, when 2-methoxyacetophenone (2b) was treated
with 1 and 0.5 equivalents of tert-butoxide for 48 h, the yield of
alcohol 3b was greater than 99%, demonstrating that the
activator can act catalytically (Table 1, Entry 9).
[a]
S. E. Varjosaari, V. Skrypai, P. Suating, J. J. M. Hurley, Prof. T. M.
Gilbert, Prof. M. J. Adler
Department of Chemistry & Biochemistry
Northern Illinois University
1425 W. Lincoln. Hwy., DeKalb, IL, 60115-2828 (USA)
E-mail: mjadler@niu.edu
Website: http://www.themjalab.com
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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COMMUNICATION
Figure 2. Scope of the reduction of ketones with 1-hydrosilatrane (1)
The scope of this reaction is broad, as seen in Figure 2:
ketones bearing electron donating groups such as methoxy,
allyloxy, and phenyl (2b-f), inductively electron withdrawing
groups such as halides as in (2g-h), and strong electron
withdrawing groups such as a nitro group (2i) can be reduced in
good to excellent yield. Potentially reactive nitro (3i) and allyl
(3e) substituents were tolerated well by the system; a trial
reaction with a single α,β-unsaturated carbonyl (chalcone)
unfortunately yielded an inseparable mixture of products.
Substitution at the α position is also acceptable (2j-l), even when
the substituent is an arene (2m-p). The system is not limited to
phenylketones, as can be seen with the reduction of
cyclohexanone (2q), heptanone (2r), and octanone (2s). The
isolated yields for the aliphatic alcohols may be lower due to
their increased water solubility and hence lower recovery during
work up.
Table 1. Optimization of reaction.
Entry
Activator (eq)
Equivalents of 1
solvent
Time
(min)
Yield (%)
1
2
tBuOK(1)
tBuOK(1)
tBuOK(1)
tBuOK(1)
NaOH(1)
K2CO3(1)
TEA (1)
1.1
1.1
1.1
1.1
1.5
1.5
1.5
1.1
1.1
DMF
DCM
MeCN
THF
40
40
94
81
74
15
22
0
3
40
4
40
5
DMF
DMF
DMF
DMF
DMF
70
6
70
7
70
0
8
tBuOK(0.5)
tBuOK(0.5)
70
20
99+
9[a]
2880
The system appears to be limited by steric effects, as can be
seen by the inability of 1-hydrosilatrane to reduce the sterically
hindered carbonyl in camphor (2t). However, the bulk of
silatrane served useful in the reduction (-)-menthone (2u), which
proved to be diastereoselective: the product is almost
exclusively (+)-neomenthol (3u).
[a] The ketone reduced in this reaction was 2-methoxyacetophenone (2b).
Reagents with such high selectivity for a single diastereomer
in the reduction of (-)-menthone (2u) are scarce, and of those,
few favor the thermodynamically less stable (+)-neomenthol (3u)
(Table 2). Commonly used commercially available L-selectride
(Table 2, Entry 3) provides (+)-neomenthol but also forms a
significant amount of the undesired side product (+)-
isoneomenthol. Unlike reductions using certain bulky reducing
agents where the diastereoselectivity is solvent dependent,24 we
do not see a significant difference in our selectivity when the
solvent is changed from a polar solvent, DMF (Table 2, Entry 9),
to a nonpolar solvent such as toluene (Table 2, Entry 10). This is
likely due to the bulk of the 1-hydrosilatrane 1, which can only
approach (-)-menthone (2u) from the less sterically hindered
face in an equatorial attack (Figure 3) regardless of choice of
solvent.
Table 2. Stereoselectivity in the reduction of (-)-menthone
entry
reducing agent
NaBH4
4:3u
35:65
10:90
0:85[a]
72:28
1:99
reference
1
2
27
27
27
28
24
29
30
31
LiB(C2H5)3H
3
L-selectride
4
LiAlH4
5
Al(iPrO)(iBu)2H
PMHS/TBAF/Pcy
Pt/C.H2
6
40:60
19:81
100:0
3:97
7
8
B(C6H5)3/H2
9
1-Hydrosilatrane/tBuOK [b]
1-Hydrosilatrane/tBuOK [c]
10
1:99
[a] 15% formation of iso-neomenthol due to racemization. [b] DMF as
solvent. [c] Toluene as solvent.
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European Journal of Organic Chemistry
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COMMUNICATION
O
OH
1 (3 eq.), 5 (1 eq. pretreated
with 2 eq. NaH)
DMF, -18 °C, 3 h
2n
3n
er 87:13 (R:S)
H2N
Ph
OH
Ph
5
Figure 3. Steric hindrance on (-)-menthone.
Figure 5. Enantioselectivity in the reduction of prochiral ketone 2n.
This stereoselectivity of the reduction of 2u, as well as the
inability to do so with camphor, suggests that close proximity is
required between the hydride donor, 1, and the carbonyl. The
increased solubility of 1 in the presence of an activator and the
inherent need of an activator for a reduction to occur allows us
to propose a mechanism (Figure 4). The Lewis base activator
coordinates with the silicon, breaking the dative bond between
Due to the steric constraints of the system, it was
speculated that a chiral activator could give enantioselectivity
with prochiral ketones. As the alkoxide product largely remains
attached to the silatrane, interference of this substrate as a less
selective activator is minimized.7a (1S,2R)-(+)-1,2-diphenyl-2-
amino-1-ethanol (5) was deprotonated with sodium hydride in
situ and used as an activator for 1 in the reduction of 2-
methylbenzophenone (2n); this gave a respectable enantiomeric
ratio of 87:13 (Figure 5). We are encouraged by this isolated
result and work on further development of this asymmetric
version of the reaction is already underway. It is worth noting
that a chiral ligand could be utilized catalytically, so long as it is
preferentially released during the last step of the proposed
mechanism.
This communication reports the reduction of a broad range
of ketones with 1-hydrosilatrane (1) in excellent yields. High
diastereoselectivity of the reduction of (-)-menthone (2u) to (+)-
neomenthol (3u) was observed, consistent with a bulky reducing
intermediate. A mechanism consistent with our observations
was proposed. Unlike PMHS and (EtO)3SiH, volatile and
extremely hazardous active hydrosilane species are not formed,
therefore making 1-hydrosilatrane a much safer alternative for
large scale reactions. Enantioselectivity was observed for the
reduction of prochiral ketone 2n with 1 and a chiral activator.
Further research is underway to improve enantioselectivity as
well as to explore the reduction of other significant functional
groups.
silicon
and
nitrogen,
maintaining
the
silicon
as
pentacoordinate.25 The silicon then forms a hexacoordinate
complex with the carbonyl, at which point the hydride is
transferred to the electrophilic carbon center to reform the
26
pentacoordinate silicon.7c,
This goes on to collapse by
elimination of the Lewis base activator to form the
alkoxysilatrane. Support for this arises from the observation that
when acetophenone is reduced in the presence of tert-butoxide
activator, 1-(phenylethoxy)silatrane can be seen on the GCMS
trace and in the 1H NMR spectrum after neutral workup.[32]
The observation of intact alkoxysilatrane before workup
suggests that the mechanism is different to that of PMHS or
(EtO)3SiH activated by a Lewis base, in which highly unstable
hydrosilanes such as MeSiH3 and SiH4 are formed in situ to act
as reducing agents.7e Avoiding such volatile and reactive
intermediates renders hydrosilatrane a both safer and more
operationally friendly reducing reagent than PMHS and other
alkoxyhydrosilanes.
Following reaction but prior to workup, smaller amounts of
tert-butoxysilatrane are also seen. The fact that the reaction can
be run with catalytic amounts of tert-butoxide supports this
mechanism, and the prominence of 1-(phenylethoxy)silatrane as
the main silatrane product formed (prior to workup) implies that
little of the phenylethoxide is released during reaction and is
therefore available to act as the Lewis base activator. We
speculate that the preferencial release of one alkoxide over
another is sterically motivated, though more experimental work
is required before this could be stated with certainty.
Experimental Section
General procedure
To
a
25 mL round-bottomed flask containing
5
mL N,N-
dimethylformamide, was added 1-hydrosilatrane (0.263 g, 2.0 mmol), and
ketone (1.0 mmol). The resulting solution was stirred for 1 minute, after
which 1 M t-BuOK in THF (1.0 mmol, 1.0 mL) was added. Reaction
mixture was allowed to stir for 30 min. Reaction was quenched with 25
mL 3 M HCl, and extracted with 30 mL ethyl acetate. Organic layer was
washed with brine (50 mL x 3), and dried with anhydrous sodium
sulphate. After filtration, the solvent was removed under vacuum to yield
product. No further steps were taken for purification.
Acknowledgements
The authors thank Northern Illinois University for funding this
research.
Keywords: silanes • reduction • metal-free • diastereoselectivity
• enantioselectivity
Figure 4. Proposed mechanism.
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Entry for the Table of Contents (Please choose one layout)
KEY WORDS: Ketone Reduction
COMMUNICATION
Sami E. Varjosaari, Vladislav Skrypai,
Paolo Suating, Joseph J. M. Hurley,
Thomas M. Gilbert, and Marc J. Adler*
Page No. – Page No.
1-Hydrosilatrane: a locomotive for
efficient ketone reductions
The next ’trane out of ’tone 1-Hydrosilatrane is shown to be an effective, cheap,
safe, and easy-to-use hydride source for the efficient reduction of a variety of
ketones. Examples of both diastereoselectivity and enantioselectivity in the reaction
are also demonstrated.
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