The Asymmetric Piers Hydrosilylation

Article abstract of DOI:10.1021/jacs.6b03443

An axially chiral, cyclic borane decorated with just one C₆F₅ group at the boron atom promotes the highly enantioselective hydrosilylation of acetophenone derivatives without assistance of an additional Lewis base (up to 99% ee). The reaction is an unprecedented asymmetric variant of Piers' B(C₆F₅)₃-catalyzed carbonyl hydrosilylation. The steric congestion imparted by the 3,3′-disubstituted binaphthyl backbone of the borane catalyst as well as the use of reactive trihydrosilanes as reducing agents are keys to success.

Full text of DOI:10.1021/jacs.6b03443

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The Asymmetric Piers Hydrosilylation
Lars Süsse, Julia Hermeke, and Martin Oestreich
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b03443 • Publication Date (Web): 23 May 2016
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The Asymmetric Piers Hydrosilylation
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Lars Süsse, Julia Hermeke, and Martin Oestreich*
Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 115, 10623 Berlin, Germany
Supporting Information Placeholder
ABSTRACT: An axially chiral, cyclic borane decorated with
just one C6F5 group at the boron atom promotes the highly
enantioselective hydrosilylation of acetophenone derivatives
without assistance of an additional Lewis base (up to 99%
ee). The reaction is an unprecedented asymmetric variant of
Piers’ B(C6F5)3‐catalyzed carbonyl hydrosilylation. The steric
congestion imparted by the 3,3’‐disubstituted binaphthyl
backbone of the borane catalyst as well as the use of reactive
trihydrosilanes as reducing agents are key to success.
Piers’ discovery that B(C6F5)3 catalyzes carbonyl hydrosi‐
Figure 1. Axially chiral congeners of B(C6F5)3 for Si‒H bond
activation (LB = Lewis base).
lylation1 opened a new chapter in reduction methodology
that still continues to grow.2 Part of the fascination with this
reaction came from its at the time peculiar mechanism. Early
insight had already suggested that it proceeds through acti‐
vation of the hydrosilane reagent by B(C6F5)3 rather than
conventional Lewis pair formation with the carbonyl sub‐
strate.3 Over recent years, the full mechanistic picture
evolved,4 and η1 coordination of the Si–H bond to B(C6F5)3
followed by SN2‐Si displacement of hydride at the silicon
atom with the carbonyl group as the nucleophile is now well
accepted. The borohydride emerging from that step is the
actual reducing agent.
To refine catalyst (S)‐1∙THF, we created steric congestion
in the proximity of the boron atom by installation of phenyl
groups in the 3 and 3’ positions. These substituents had a
dramatic effect on both catalyst preparation and purification.
Introduction of the B(C6F5) unit by conventional tin–boron
exchange failed,5 and we had to develop a dummy‐ligand
strategy to overcome chemoselectivity issues [(S)‐4 → (S)‐3,
Scheme 1].15 Moreover, Lewis‐pair formation between (S)‐3
and various Lewis bases to precipitate or crystallize adducts
of type (S)‐3∙LB was hampered by the steric situation around
the boron atom in (S)‐3. We eventually succeeded using 3,3‐
dimethyloxetane (3,3‐DMO) and were able to crystallograph‐
ically characterize (S)‐3∙3,3‐DMO.15 However, considerable
experimentation was required to reliably remove stoichio‐
metrically formed 5 by precipitation and several washing
cycles [(S)‐3 → (S)‐3∙3,3‐DMO, Scheme 1]. Alternatively,
dimethyl sulfide (DMS) worked equally well, and (S)‐3∙DMS
was isolated with less than 1% tin contamination [(S)‐3 →
(S)‐3∙DMS, Scheme 1; see the Supporting Information for the
molecular structure of (S)‐3∙DMS]. Although both complexes
of (S)‐3 as well as the free borane (S)‐3 (burdened with 5)
induced similar levels of enantioselection (vide infra), we
decided to continue with (S)‐3∙DMS.
An asymmetric variant of the Piers hydrosilylation would
therefore require a chiral B(C6F5)3 congener that is sufficient‐
ly electron‐deficient to promote the Si–H bond activation
and meets the challenge of inducing enantioselectivity as its
borohydride. For this, we introduced axially chiral (S)‐1∙THF
with one C6F5 group at the boron atom a few years ago (Fig‐
ure 1, left)5 but enantioinduction was low (≤15% ee).6 Sub‐
stantially better levels of enantioselection were obtained with
(S)‐1∙THF in the related catalytic hydrosilylation of imines7
(≤62% ee).8 Even higher enantiomeric excesses (≤87% ee)
were achieved by borrowing from the concept of frustrated
Lewis pairs (FLPs9):10 Klankermayer and co‐workers em‐
ployed an FLP∙H2 adduct composed of a terpene‐derived
borane and a bulky phosphine in the imine hydrosilylation;
the hydrosilylation of acetophenone was again inferior (37%
ee).11 The FLP strategy was also successful in the hydrosilyla‐
tion of α‐keto carbonyl and carboxyl compounds (>99% ee),
using one of Du’s in‐situ‐generated catalysts (S)‐2 (Figure 1,
right).12,13 The same catalytic setup afforded 42% ee in the
reduction of acetophenone. To date, the asymmetric Piers
hydrosilylation catalyzed by an electron‐deficient borane
alone14 is elusive, and we disclose here a solution to this long‐
standing problem.
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Scheme 1. Catalyst Preparation
Table1.Optimization of the Carbonyl Hydrosilylation
Ph
6
7
8
SiMe3
SiMe3
Sn
9
Ph
10
11
12
13
14
15
16
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(S)-4 (Ref 15)
entry hydrosilane equiv solvent
conv.
(%)a
ee
(%)b
(C6F5)BCl2 CH2Cl2
(1.2 equiv)
r.t.
1
Ph3SiH
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
3.0
3.0
5.0
1,2‐F2C6H4
1,2‐F2C6H4
1,2‐F2C6H4
1,2‐F2C6H4
—
—
—
—
—
—
—
—
Ph
2
Me2PhSiH
EtMe2SiH
Ph2SiH2
MePhSiH2
PhSiH3
3
Cl
SiMe3
SiMe3
+
B
C6F5
Sn
4
5
Cl
1,2‐F2C6H4 quant. 28
1,2‐F2C6H4 quant. 81
1,2‐F2C6H4 quant. 87
TMSM2SnCl2
5
Ph
(S)-3: 94%
[w/ <50% of 5]
6
7
MesSiH3
t‐BuSiH3
PhSiH3
8
9
10
11
12
1,2‐F2C6H4 traces
—
DMS
3,3-DMO
1,2‐F2C6H4 quant. 93
1,2‐F2C6H4 quant. 93
n-hexane
r.t.
n-hexane
r.t.
PhSiH3
Me
Ph
Me
Ph
B
Me
PhSiH3
neat
quant. 93
S
O
Me
C6F5
PhSiH3
neat
quant. 93
B
aDetermined by GLC analysis using tetracosane as internal
C6F5
b
standard. Determined by HPLC analysis using a chiral sta‐
Ph
Ph
tionary phase.
(S)-3·3,3-DMO: 80%
[w/ ~1% of 5 after two washes
with n-hexane]
(S)-3·DMS: 53%
[w/ <1% of 5 after six washes
with n-hexane:DMS 20:1]
(X-ray SI)
Application of the optimized procedure (Table 1, entry 11)
to ether‐coordinated (S)‐3∙3,3‐DMO required double the
reaction time; the enantiomeric excess (90% ee) was in the
same range. Importantly, the free borane (S)‐3 in an almost
equimolar mixture with tin byproduct 5 catalyzed the hy‐
drosilylation as efficiently as (S)‐3∙DMS with 92% ee. Hence,
we believe that neither Lewis base interferes in the reaction
as is the case with phosphine additives.11,12
(X-ray Ref 15)
With catalyst (S)‐3∙DMS, we tested representative hy‐
drosilanes as reductants in the hydrosilylation of acetophe‐
none [6 → (S)‐7, Table 1, entries 1–8]. Not surprisingly, mon‐
ohydrosilanes including EtMe2SiH were too sterically hin‐
dered. This was also true for Ph2SiH2 but with MePhSiH2
carbonyl compound 6 was fully converted within two days,
affording (S)‐7 with 28% ee. Trihydrosilanes such as PhSiH3
and MesSiH3 performed even better, reaching enantioselec‐
tivities of 81 and 87% ee, respectively; t‐BuSiH3 did not react.
The use of an equimolar amount of the trihydrosilane is
likely to be detrimental to enantioinduction as intermediate
chiral alkoxy‐substituted hydrosilanes will potentially act as
reductants (Table 1, entry 6 vs entries 9–12). With 2.0 instead
of 1.0 equiv of PhSiH3, the level of enantiocontrol was im‐
proved to 93% ee. No further increase of the enantiomeric
excess was seen with more hydrosilane. It made no difference
whether the catalysis was run in 1,2‐F2C6H4 as solvent or
neat. The catalayst loading also had an effect on conversion
and enantioinduction (for a discussion of this observation,
see below):7c 1.0 mol % resulted in 80% ee at 42% conversion
and 5.0 mol % yielded 94% ee at full conversion (both within
one day; see the Supporting Information for details).
We then examined various electronically modified aceto‐
phenone derivatives 8–14, and the effects were substantial
(Scheme 2). Compared to parent 6 (full conversion in one
day), CF3‐ and NO2‐substituted 8 and 9 were less reactive
(four and two days, respectively). Conversely, MeO‐
substituted 14 showed full conversion in one day. The differ‐
ence in enantioselectivity between these extremes was even
more pronounced with 80% ee for 9 but 28% ee for 14. Re‐
markably, the carboxyl group in 10 was tolerated, and im‐
pressive 98% ee in 87% isolated yield were reached. The
results for Cl‐ and Me‐substituted 11 and 12 were also satis‐
factory but the enantiomeric excess collapsed for the corre‐
sponding Ph‐substituted acetophenone 13. Steric hindrance
was also detrimental to both reactivity and enantioinduction;
mesityl‐substituted 15 afforded 24% conversion after four
days and no better than 17% ee. A similar result was obtained
from the systematic investigation of the three regioisomeric
monobrominated acetophenones 16–18. The para‐ and meta‐
substituted compounds 16 and 17 reacted as good as aceto‐
phenone itself, and the level of enantioselection was excel‐
lent (95% ee and 99%, respectively). However, ortho substi‐
tution as in 18 again slowed down the hydrosilylation, and
enantioinduction dropped to 73% ee. Replacing the methyl
by a benzyl or cyclohexyl group at the carbonyl carbon atom
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led to far less reactive 19 and 20, and asymmetric induction
aDetermined by GLC analysis using mesitylene as internal
gradually decreased with increasing steric bulk. Good enan‐
tiomeric excess was seen with β‐naphthyl derivative 21.
Likewise, the enantiomeric excess measured for benzophe‐
none 22 as substrate was even lower. These are the current
limitations of the method. — The discrepancy between con‐
version and isolated yield is mainly due to competing deoxy‐
genation, known to occur with B(C6F5)3/hydrosilane combi‐
nations.16
standard. bDetermined by HPLC analysis using chiral sta‐
c
tionary phases. For better solubility, double the amount of
PhSiH3 used. dAddition of 1,2‐F2C6H4 as solvent to secure
homogeneous solution.
Both α‐diketones and α‐keto esters were the privileged
substrates for Du’s catalytic system (S)‐2/HB(C6F5)2 in the
presence of Cy3P (91% yield and >99% ee).12 Remarkably,
benzil was completely inert against our catalyst (S)‐3∙DMS,
and ethyl phenylglyoxylate was reduced within four days yet
without any enantioselectivity (not shown). These results
emphasize that Du’s and our catalyst system are complemen‐
tary.
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Scheme 2. Scope and Limitations of the Enantioselec‐
tive Carbonyl Hydrosilylationa,b
(S)-
3·DMS (2.4 mol %)
OH
O
PhSiH3 (3.0 equiv)
R2
R2
We had observed before that conversion and enantiomeric
excess are dependent on the amount of catalyst employed
(see above). Moreover, several of the hydrosilylations dis‐
played slightly deviating values for the enantiomeric excess
with 2.4 mol % fixed catalyst loading when conversions were
lower or higher than those reported in Scheme 2. We inter‐
pret these findings on the basis of our recent mechanistic
investigation of the cognate ketimine hydrosilylation.7c In
this work, we demonstrated that deprotonation of the inter‐
mediate α‐C–H‐acidic silyliminium ion by the unreacted
imine substrate forms the corresponding iminium ion. Both
iminium ions engage in the enantioselectivity‐determining
borohydride reduction, resulting in two competing reaction
pathways with potentially different stereochemical out‐
comes. The same scenario applies to the present ketone
hydrosilylation where the catalytic cycle proceeds through
either a silylcarboxonium ion I or a “hidden” protonated
carboxonium ion II (Scheme 3).
R1
R1
neat
r.t.
6 and 8–22
(S)-7 and (S)-23–(S)-37
(after hydrolysis)
OH
OH
OH
Me
Me
Me
F3C
O2N
(S)- (from
92% conv. in four days full conv. in two days
c
7
6
23
(S)- (from
8
24
9
)
(S)- (from
)
)
full conv. in one day
62% yield, 93% ee
57% yield, 82% ee
56% yield, 80% ee
OH
OH
OH
Me
Me
Me
MeO2C
Cl
Me
(S)-25 (from 10)d
full conv. in one day
87% yield, 98% ee
(S)-26 (from 11)
full conv. in one day
63% yield, 95% ee
(S)-27 (from 12)
full conv. in two days
67% yield, 85% ee
Scheme 3. Generation of Another Activated Carbonyl
Group by α‐Deprotonation (Borohydride Coun‐
teranion Omitted for Clarity)
OH
Me
OH
Me
OH
Me
Me
Ph
MeO
Me
Me
(S)-28 (from 13)d
full conv. in two days
64% yield, 70% ee
(S)-29 (from 14)
full conv. in one day
64% yield, 28% ee
(S)-30 (from 15)
24% conv. in four days
12% yield, 17% ee
OH
OH
Br
OH
Me
Br
Me
Me
To summarize, we developed an enantioselective variant of
Piers’ B(C6F5)3‐catalyzed carbonyl hydrosilylation.1 A combi‐
nation of a binaphthyl‐based boron catalyst with just one
C6F5 group at the boron atom and reactive trihydrosilanes as
the stoichiometric reductant were crucial for achieving ac‐
ceptable conversion (one day) and high enantioselection (up
to 99% ee). The new method distinguishes itself from previ‐
ous FLP‐type approaches11–13 as no additional Lewis base is
needed. As in the original protocol by Piers,1 the borane
catalyst alone promotes the hydrosilylation.
Br
(S)-31 (from 16)
full conv. in one day
63% yield, 95% ee
(S)-32 (from 17)
full conv. in one day
78% yield, 99% ee
(S)-33 (from 18)
full conv. in four days
45% yield, 73% ee
OH
OH
(S)-34 (from 19)
55% conv. in four days
40% yield, 74% ee
(S)-35 (from 20)
29% conv. in four days
24% yield, 62% ee
ASSOCIATED CONTENT
Supporting Information
OH
Me
OH
1
11
Experimental details, characterization data, as well as H, B,
13C, and 19F NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Br
(S)-36 (from 21)
full conv. in one day
77% yield, 80% ee
(S)-37 (from 22)c
full conv. in four days
64% yield, 14% ee
AUTHOR INFORMATION
Corresponding Author
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martin.oestreich@tu‐berlin.de
Notes
5
The authors declare no competing financial interest.
6
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ACKNOWLEDGMENT
9
M.O. is indebted to the Einstein Foundation (Berlin) for an
endowed professorship. We thank Dr. Elisabeth Irran (TU
Berlin) for the X‐ray analysis.
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REFERENCES
(1) Parks, D. J.; Piers, W. E. J. Am. Chem. Soc. 1996, 118, 9440–9441.
(2) For reviews, see: (a) Oestreich, M.; Hermeke, J.; Mohr, J. Chem.
Soc. Rev. 2015, 44, 2202–2220. (b) Piers, W. E.; Marwitz, A. J. V.;
Mercier, L. G. Inorg. Chem. 2011, 50, 12252–12262.
(3) Parks, D. J.; Blackwell, J. M.; Piers, W. E. J. Org. Chem. 2000,
65, 3090–3098.
(4) (a) Rendler, S.; Oestreich, M. Angew. Chem., Int. Ed. 2008, 47,
5997–6000. (b) Sakata, K.; Fujimoto, H. J. Org. Chem. 2013, 78, 12505–
12512. (c) Houghton, A. Y.; Hurmalainen, J.; Mansikkamäki, A.; Piers,
W. E.; Tuononen, H. M. Nat. Chem. 2014, 6, 983–988.
(5) Mewald, M.; Fröhlich, R.; Oestreich, M. Chem.‒Eur. J. 2011, 17,
9406–9414.
(6) Mewald, M. Ph.D. Thesis, Westfälische Wilhelms‐Universität
Münster, Germany, 2012.
(7) (a) Blackwell, J. M.; Sonmor, E. R.; Scoccitti, T.; Piers, W. E.
Org. Lett. 2000, 2, 3921–3923. (b) Hog, D. T.; Oestreich, M. Eur. J.
Org. Chem. 2009, 5047–5056. (c) Hermeke, J.; Mewald, M.; Oe‐
streich, M. J. Am. Chem. Soc. 2013, 135, 17537–17546.
(8) (a) Mewald, M.; Oestreich, M. Chem.‒Eur. J. 2012, 18, 14079–
14084. For the enantioselective hydrosilylation catalyzed by (S)‐2 (R
= 3,5‐(3,5‐tBu2C6H3)2; ≤82% ee), see: (b) Zhu, X.; Du, H. Org. Biomol.
Chem. 2015, 13, 1013–1016.
(9) For authoritative reviews, see: (a) Stephan, D. W. J. Am. Chem.
Soc. 2015, 137, 10018–10032. (b) Stephan, D. W.; Erker, G. Angew.
Chem., Int. Ed. 2015, 54, 6400–6441.
(10) Asymmetric FLP‐type hydrogenation is closely connected to
the present hydrosilylation, and Klankermayer’s and Du’s chiral
boranes have been applied in both transformations. For reviews, see:
(a) Feng, X.; Du, H. Tetrahedron Lett. 2014, 55, 6959–6964. (b) Chen,
D.; Klankermayer, J. In Frustrated Lewis Pairs II, Expanding the
Scope; Erker, G., Stephan, D. W., Eds.; Topics in Current Chemistry
334; Springer: Heidelberg, Germany, 2013; pp 1–26. For asymmetric
imine hydrogenation, see: (c) Chen, D.; Wang, Y.; Klankermayer, J.
Angew. Chem., Int. Ed. 2010, 49, 9475–9478. (d) Sumerin, V.; Cherni‐
chenko, K.; Nieger, M.; Leskelä, M.; Rieger, B.; Repo, T. Adv. Synth.
Catal. 2011, 353, 2093–2110. (e) Stephan, D. W.; Greenberg, S.; Gra‐
ham, T. W.; Chase, P.; Hastie, J. J.; Geier, S. J.; Farrell, J. M.; Brown, C.
C.; Heiden, Z. M.; Welch, G. C.; Ullrich, M. Inorg. Chem. 2011, 50,
12338–12348. (f) Ghattas, G.; Chen, D.; Pan, F.; Klankermayer, J.
Dalton Trans. 2012, 9026–9028.
(11) Chen, D.; Leich, V.; Pan, F.; Klankermayer, J. Chem.‒Eur. J.
2012, 18, 5184–5187.
(12) Ren, X.; Du, H. J. Am. Chem. Soc. 2016, 138, 810–813.
(13) The net outcome of the FLP‐type hydrogenation of silyl enol
ethers is that of the carbonyl hydrosilylation: (a) Wei, S.; Du, H. J.
Am. Chem. Soc. 2014, 136, 12261–12264. (b) Ren, X.; Li, G.; Wei, S.; Du,
H. Org. Lett. 2015, 17, 990–993.
(14) For enantioselective imine hydrogenation catalyzed by elec‐
tron‐deficient boranes without the need for a bulky phosphine as an
additive, see: (a) Chen, D.; Klankermayer, J. Chem. Commun. 2008,
2130–2131. (b) Liu, Y.; Du, H. J. Am. Chem. Soc. 2013, 135, 6810–6813.
(15) Hermeke, J.; Mewald, M.; Irran, E.; Oestreich, M. Organome‐
tallics 2014, 33, 5097–5100.
(16) (a) Gevorgyan, V.; Rubin, M.; Benson, S.; Liu, J.‐X.; Yamamo‐
to, Y. J. Org. Chem. 2000, 65, 6179‒6186. (b) Nimmagadda, R. D.;
McRae, C. Tetrahedron Lett. 2006, 47, 5755‒5758.
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