Exploring Multistep Continuous-Flow Hydrosilylation Reactions Catalyzed by Tris(pentafluorophenyl)borane

Article abstract of DOI:10.1002/adsc.201700349

Exploring the combination of continuous-flow processes with the boron Lewis acid catalyzed hydrosilylation of aldehydes and ketones has delivered a robust and generally applicable reaction protocol. Notably this approach permits ready access to high temperatures and pressures and thus allows improved reactivity of substrates that were previously recalcitrant under the traditional approach. Efforts to quench the output from the flow reactor with water showed surprising tolerance leading to the application of continuous-flow systems in multistep imine formation/hydrosilylation processes to generate the corresponding secondary amines from their aldehyde and aniline precursors. (Figure presented.).

Full text of DOI:10.1002/adsc.201700349

Title: Exploring Multistep Continuous Flow Hydrosilylation Reactions
Catalyzed by Tris(pentafluorophenyl)borane
Authors: Lewis Wilkins, Joseph Howard, Stefan Burger, Louis Frentzel-
Beyme, Duncan Browne, and Rebecca Melen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700349
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10.1002/adsc.201700349
Advanced Synthesis & Catalysis
COMMUNICATION
Exploring Multistep Continuous Flow Hydrosilylation Reactions
Catalyzed by Tris(pentafluorophenyl)borane
Lewis C. Wilkins, Joseph L. Howard, Stefan Burger, Louis Frentzel-Beyme, Duncan L. Browne* and
Rebecca L. Melen*
School of Chemistry, Main Building, Park Place, Cardiff University, Cardiff, CF10 3AT, U.K.
E-mail: MelenR@Cardiff.ac.uk or DLBrowne@cardiff.ac.uk
Supporting information for this article can be found under:
Abstract: Exploring the combination of continuous-flow processes
with the boron Lewis acid catalyzed hydrosilylation of aldehydes and
ketones has delivered a robust and generally applicable reaction
protocol. Notably this approach permits ready access to high
temperatures and pressures and thus allows improved reactivity of
substrates that were previously recalcitrant under the traditional
approach. Efforts to quench the output from the flow reactor with water
showed surprising tolerance leading to the application of continuous-
flow systems in a multistep imine formation/hydrosilylation processes
to generate the corresponding secondary amines from their aldehyde
and aniline precursors.
Scheme 1. Previous work into the mechanism of borane
catalyzed hydrosilylation.
Keywords: hydrosilylation; frustrated Lewis pairs; catalysis; multistep
continuous flow; B(C6F5)3
In certain instances this symbiotic relationship has led to
increased conversion, selectivity and reaction rates, but perhaps
more importantly, flow chemistry can provide an automated
Highly Lewis acidic boranes containing perfluorinated aryl
groups,
including
the
archetypal
Lewis
acid
platform that permits machines to conduct laborious or repetitive
processes[11] whilst also enabling multistep syntheses.[12] These
systems are able to negate many manual handling steps,[13] and
through the construction of setups with interchangeable modular
sections, vast libraries of compounds can be achieved. In
addition, an important application of continuous-flow processing
is the permittance of high temperatures and pressures, higher
than is conventionally tolerated under standard batch reactions.
The superheating of solvents under high pressures more often
leads to faster reaction rates being observed, making the adoption
of such techniques incredibly attractive to the synthetic chemist.
Indeed, the use of a back-pressure regulator (BPR) allows the
pressure of the reactor coil to be maintained throughout the
reactor setup enabling easily scalable high temperature and
pressure conditions.[14] This also highlights a further potential
benefit of continuous-flow reactor technology, that is to maintain
an improved safety profile whilst conducting ‘forbidden’
chemistries.[15] This current work explores the combination of
the two fields of main group catalysis and continuous-flow
chemistry for a multistep condensation/hydrosilylation processes.
tris(pentafluorophenyl) borane, B(C6F5)3, have enjoyed
widespread applications in both organic and organometallic
chemistry.[1] Research in one of our groups has focused on the
use of B(C6F5)3 in the reactions with various unsaturated
frameworks[2] while others have proven it to be an excellent
catalyst for the installation of C–Si,[3] O–Si[4] and even N–Si
bonds (en route to hydrogenation).[5] Pioneering work in this
field by Piers et al. demonstrated how B(C6F5)3 can catalyze the
hydrosilylation of aromatic aldehydes, ketones and esters.[4] It
was seen through quantitative rate studies that this
transformation proceeds through an alternative mechanism to
that of conventional Lewis acid catalysis (Scheme 1).[5a,6] In
these initial findings, the hydrosilylated products were recovered
in good to excellent yields (ca. 80%). These results were later
reinforced by the work of Oestreich et al. through further studies
expounding the SN2-Si mechanism by which this hydrosilylation
occurs,[7] with in-depth computational analyses by Fujimoto et al.
supporting this hypothesized silane activation by B(C6F5)3.[8]
Whilst these established synthetic routes have been
explored using traditional batch methods, they have not
previously been investigated using novel processing methods,
such as continuous-flow. In recent years, the adoption of
continuous-flow techniques has increased amongst both
academic and industrial research groups.[9] In light of this,
continuous-flow reactors have become more ubiquitous as the
advantages offered by such systems are becoming recognized
across different fields.[10]
Prior to translating into
a
continuous process,
investigations were conducted through conventional techniques
to check for incompatibilities. Acetophenone was selected as the
model ketone for testing. In agreement with previous findings,
optimal conditions include 2 mol% catalyst loading with a
concentration of 0.2 M in toluene, notably this procedure did not
lead to any formation of precipitates or particulates. To achieve
comparable conditions for use in flow, 5 mL of a 0.4 M solution
of ketone/aldehyde and silane was combined with 5 mL of the
B(C6F5)3 solution (2 mol%) to produce a reaction stream of 0.2
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10.1002/adsc.201700349
Advanced Synthesis & Catalysis
COMMUNICATION
M. The silane/substrate and borane streams were combined using
a T-piece resulting in a combined flow rate of 0.166 mL/min.
The combined reaction stream was then passed through a
reaction coil (5 mL) giving a residence time of 30 minutes.
Collection of the product stream commenced after 36 mins under
presumed steady-state conditions.
and aldehyde moieties featuring activated aryl groups (1g and 2g
where R = p-MeOC6H4, Figures 1 and 2). These results agree
with previous findings whereby a deactivated aldehyde or ketone
is necessary to facilitate effective hydride transfer.[4]
Initial analysis via 1H NMR spectroscopy returned
agreeable results for the screening of acetophenone at r.t. giving
good conversion (85%). This was optimized further by
conducting the reaction at 60 °C, which resulted in essentially
quantitative conversion to the silyl ether 1a (98%). At this
juncture, it was imperative that the correct catalyst quenching
protocol was developed to ensure that the conversion
measurement was a true representation of the flow process and
not a combination of the flow and continued reaction in the
collection vessel. In order to design this quenching protocol,
three methods were explored to irreversibly bind the borane
catalyst; 1) the addition of water, 2) dropping into a slurry of CsF
in MeCN, and 3) passing through a short silica plug (Figure 1).
It was observed that reactivity continued with the former two
processes, NMR ratios of products to starting materials
continued to change following the ‘quench’ procedure. The
catalyst was also observable in the 11B and 19F NMR spectrum.
Indeed, this observation has recently been reported by both
Ingleson and Ashley.[16] However, when being filtered through
a short silica plug, any further catalytic activity was prevented
and the catalyst was completely removed from the crude reaction
mixture as evidenced in the 11B and 19F NMR spectra.
Figure 2. Continuous-flow hydrosilylation of ketones
Conversion measured via 1H NMR spectroscopy.
Figure 1. Quenching protocols to terminate catalytic activity.
With an optimized quenching protocol, the scope of the
process was then explored to see if a range of reactants would
remain in solution in the flowing stream. Across a small range of
both ketone and aldehyde substrates spanning electronic and
steric properties, the reaction proceeded successfully (>90%)
and importantly, no precipitate formation was observed. As
originally reported by Piers, we have found ketones to be more
reactive to reduction via this approach than aldehydes. This is
particularly notable in the example of the mesityl derivatives, 1d
and 2d, where application of identical conditions led to
conversions of 87% and 62% for the ketone and aldehyde
derivatives respectively (Figures 2 and 3). This reversal of the
typical reactivity is truly remarkable. Notably, both the 1,3
bisacetylbenzene and homobenzylic ketone substrates
underwent reduction in excellent conversion. Relatively low Figure 3. Continuous-flow hydrosilylation of aldehydes using.
conversions (78% and 55%) were seen for the respective ketone
Conversion measured via 1H NMR spectroscopy.
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10.1002/adsc.201700349
Advanced Synthesis & Catalysis
COMMUNICATION
It was hypothesized that simple modification of the reactor
setup could overcome this shortfall in reaction performance.
Modifications consisted of the inclusion of high pressure HPLC
A less bulky silane (Me2PhSiH) was used during this
method in order to maximize reactivity and reduce any
unfavorable steric occlusion brought about by the substituent on
pumps and a back-pressure regulator (BPR) thus permitting easy nitrogen and the newly installed silane moiety.[17] A mixture of
reach of higher pressures and thus temperatures past the aldehyde (0.4 M) and Me2PhSiH (0.48 M) in toluene was
atmospheric pressure boiling point of the solvent. With this
modified setup, the reactor could hydrosilylate p-anisaldehyde
within 5 minutes affording a 67% conversion at a reaction
temperature of 150 °C and 130 PSI (Figure 4).
combined with a stream of the aniline substrate in toluene (0.48
M) using a T-piece joint. Passage through a short residence coil
afforded the requisite imine formation whereupon a 2 mol%
stream of B(C6F5)3 was combined, this reaction mixture then
Returning to our earlier observations on quenching, we proceeded to reactor coil 2, which was heated to 150 °C with a
were intrigued by the idea that the borane remained catalytically
active in the presence of water. Thus our investigations turned to
applying this setup to condensation reactions whereby the side
formation of water would not impede catalytic activity.[16]
Therefore, the reactor setup was again adapted, now for a
multistep process whereby a third stream was included to deliver
a third reagent.[12] This modification allowed us to generate
residence time of 10 minutes, the output stream was cooled to
ambient temperature before passing through the back-pressure
regulator (130 PSI), and filtering through a plug of silica to
remove the catalyst.
In general, this method generates the desired secondary
amine with good conversions as measured by 1H NMR
spectroscopy as well as isolated yields, up to 89%, with the
secondary imines from their aniline and aldehyde counterparts in exceptions being strongly electron withdrawing or donating
the first reaction coil (along with the H2O byproduct) followed
by B(C6F5)3 catalyzed hydrosilylation in the second reactor coil
(Figure 5).
groups on the aniline reagent (p-OMe = 45%, p-CF3 = 34%).
Indeed, in the case of the p-CF3 substituted aniline the product
stream also contained hydrosilylated aldehyde, the system could
likely be independently optimized for these electronic biases.
Increasing the length or temperature of reactor coil 1 would
result in more complete conversion to the imine prior to the
second step reaction. Although this pathway proceeds via a
condensation reaction, the borane does not appear to suffer from
any ‘poisoning’ from the water by-product during the reaction.
The radial chart (Figure 5) shows a number of reaction
parameters comparing batch to flow processing of this tandem
imine formation/hydrosilylation process. Clearly the flow
approach allows more convenient access to the lesser-used
processing windows of high temperatures and pressures and thus
delivers enhanced conversions with the same loading of catalyst
but in a significantly shorter reactor time.
Figure 4. Comparison between low pressure/temperature and
high pressure/temperature systems. Conversion measured via 1H
NMR spectroscopy.
Figure 5. Tandem B(C6F5)3 catalysis to give 3 alongside radial chart comparing batch and flow systems. Conversion measured
via 1H NMR spectroscopy isolated yields indicated in parentheses.
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10.1002/adsc.201700349
Advanced Synthesis & Catalysis
COMMUNICATION
In summary, we have demonstrated the productive
combination of main-group chemistry with multistep flow
techniques. This has led to the rapid processing of substrate
examples that are problematic under more traditional conditions.
Finally, we have demonstrated that the release of water as a
byproduct through a condensation reaction is compatible with a
B(C6F5)3 catalyst and thus a multistep flow process for the
formation of secondary amines was realized.
References:
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Experimental Section
General procedure for hydrosilylation of aldehydes
and ketones
A solution of triphenylsilane (1.0 equiv.) and aldehyde or ketone
(1.0 equiv.) (0.4 M, toluene) was prepared along with a separate
solution of tris(pentafluorophenyl)borane (0.008 M, 2 mol%,
toluene). 5 mL aliquots of each solution were combined at
matched flow-rates using a T-piece adapter via syringe pump
with a combined flow rate of 0.166 mLmin-1. The mixed reaction
stream then proceeded to a 5 mL tubular reaction coil where it
was heated to 60 °C and left to collect as waste for 36 minutes
(to allow the system to reach steady-state) before the output was
directed through a short plug of silica gel (to remove catalyst)
and collected in a flask for 12 minutes (2 mL). The solvent was
removed in vacuo followed by NMR spectroscopy to ascertain
the conversion.
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General procedure for tandem imine formation,
hydrosilylation and hydrolysis.
A
solution of the aldehyde (0.4 M, 1 equiv.) and
dimethylphenylsilane (0.48 M, 1.2 equiv., toluene), aniline (0.48
M, 1.2 equiv., toluene) and B(C6F5)3 (0.008 M, 2 mol%, toluene)
were loaded into the sample loop of stream A, B and C
respectively. The pumps were set to a flow rate of 0.17 mLmin-1
and the temperature of the heated coil set to 150 °C. Streams A
and B were set to inject, followed by stream C after 41 s. After
waiting for 7 mL (14 min) to be collected as waste (to allow the
system to reach steady-state), the output was directed through a
plug of silica gel (to remove the catalyst) and the solution
collected for 8 minutes (4 mL). The solvent was removed under
reduced pressure and mesitylene (74 μL, 0.064 g, 0.53 mmol)
added as an internal standard. NMR conversions were
1
determined by H NMR spectroscopy. Isolated products were
obtained after column chromatography on silica gel using an
ethyl acetate/petroleum ether eluent (1:4 for 3a, 1:9 for 3d) and
drying in vacuo.
Acknowledgement:
We thank Cardiff University for generous support, The Royal
Society for
a Research Grant (D.L.B., award number
RG150376), the ERASMUS+ program (support of S.B. and L.F-
B.) and Cambridge Reactor Design for a studentship to J.L.H.
We thank the EPSRC UK National Mass Spectrometry Facility
at Swansea University for mass spectrometry measurements.
Notes and references
Corresponding Authors:
Dr Rebecca L. Melen:
E-mail: MelenR@cardiff.ac.uk
Dr Duncan L. Browne:
[17] a) J. M. Blackwell, E. R. Sonmor, T. Scoccitti, W. E. Piers, Org.
Lett. 2000, 2, 3921-3923; b) D. Chen, V. Leich, F. Pan, J.
Klankermayer, Chem. Eur. J. 2012, 18, 5184-5187.
E-mail: DLBrowne@cardiff.ac.uk
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700349
Advanced Synthesis & Catalysis
COMMUNICATION
COMMUNICATION
Lewis C. Wilkins, Joseph L. Howard,
Stefan Burger, Louis Frentzel-Beyme,
Duncan L. Browne*, and Rebecca L.
Melen*
Exploring Multistep Continuous-Flow
Hydrosilylation Reactions Catalyzed
by Tris(pentafluorophenyl)borane
Exploring the combination of continuous-flow and multistep processes with the
boron Lewis acid catalyzed hydrosilylation of aldehydes, ketones and in situ
generated imines has delivered a robust and generally applicable reaction
protocol for the synthesis of reduced products in good to excellent yields.
This article is protected by copyright. All rights reserved.