Auto-Tandem Catalysis with Frustrated Lewis Pairs for Reductive Etherification of Aldehydes and Ketones

Article abstract of DOI:10.1002/anie.201700231

Herein we report that a single frustrated Lewis pair (FLP) catalyst can promote the reductive etherification of aldehydes and ketones. The reaction does not require an exogenous acid catalyst, but the combined action of FLP on H₂, R-OH or H₂O generates the required Br?nsted acid in a reversible, “turn on” manner. The method is not only a complementary metal-free reductive etherification, but also a niche procedure for ethers that would be either synthetically inconvenient or even intractable to access by alternative synthetic protocols.

Full text of DOI:10.1002/anie.201700231

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International Edition: DOI: 10.1002/anie.201700231
German Edition: DOI: 10.1002/ange.201700231
Frustrated Lewis Pairs
Hot Paper
Auto-Tandem Catalysis with Frustrated Lewis Pairs for Reductive
Etherification of Aldehydes and Ketones
Mꢀria Bakos, ꢁdꢀm Gyçmçre, Attila Domjꢀn, and Tibor Soꢂs*
In memory of George A. Olah
Abstract: Herein we report that a single frustrated Lewis pair
(FLP) catalyst can promote the reductive etherification of
aldehydes and ketones. The reaction does not require an
exogenous acid catalyst, but the combined action of FLP on
H2, R-OH or H2O generates the required Brønsted acid in
a reversible, “turn on” manner. The method is not only
a complementary metal-free reductive etherification, but also
a niche procedure for ethers that would be either synthetically
inconvenient or even intractable to access by alternative
synthetic protocols.
nisms, a hydrogenation and a Brønsted acid catalysis,
promoted by a single FLP catalyst. The synthetic merit of
this process is that it enables the simple construction of
various ethers that would be either difficult or even intract-
able to access.
Arguably one of the principal synthetic transformations in
organic chemistry has been the construction of dialkyl ether
linkage.[8] Despite the wealth of ether linkage forming
methodologies, there is still a room for improvement in
reaction efficiency and generality. Reductive etherification
represents[9,10] an ideal methodology because this reaction can
overcome many of the synthetic challenges of the venerable
Williamson reaction[11] or acid-mediated dehydration pro-
cesses.[12] Although various silicon- and boron-based reducing
agents have been used in reductive etherifications,[9] the
application of a more atom-economic alternative, H2 has not
gained widespread utility because the employed precious
metal catalysts have had limited functional group tolerance
and protocols often necessitated harsh reaction conditions.[10]
In a dual attempt to further the evolution of the ether
bond formation and the metal-free FLP hydrogenation, we
sought to exploit frustrated Lewis pair catalysis for reductive
etherification reaction (Scheme 1). However, the adaptation
C
atalytic hydrogenation is one of the most versatile and
useful synthetic transformations used in academic and
industrial settings.[1] The predominantly used catalysts based
on platinum group metals, however, raise ever-growing
toxicological, environmental, and economic concerns. There-
fore, increasing efforts have recently been devoted to design-
ing and discovering catalysts that are resting on non-precious
elements.[2]
Among these alternatives, frustrated Lewis pair (FLP)
hydrogenation has attracted widespread attention as an
unprecedented metal-free approach. The applied catalyst
systems are consisting of Lewis acid–base pairs that are
prevented from the classical donor–acceptor adduct forma-
tion by steric factors. This unique feature enabled the
heterolytic activation of hydrogen, which reactivity promoted
the development of catalytic FLP hydrogenations.[3–5] The
utility of the incipient catalysts was limited and subsequent
researches were motivated by the prospect of expanding the
scope of FLP hydrogenation and solving the problems related
to functional group tolerance. These efforts have resulted in
the valorization of FLP hydrogenation and triggered to
unlock even more of its potential via frustrated Lewis pair
tandem catalysis.[6,7] In this variant, FLP hydrogenation is
coupled with additional catalytic processes, thus sequential
transformation of the substrate occurs in two or more
mechanistically distinct processes. Along this line, we report
herein the development of a metal-free reductive ether-
ification method that involves two distinct catalytic mecha-
Scheme 1. FLP catalyzed carbonyl reductions with H2.
of FLPs to reductive etherification was far from being
straightforward because of substrate and product inhibition
of the highly oxophilic, hard-type Lewis acid component of
FLPs. As exemplified, catalytic FLP reduction of carbonyls
has been a long unsolved problem that was only realized two
years ago by Stephanꢀs and Ashleyꢀs groups.[13] Subsequently,
the challenge of water sensitivity of FLPs was resolved.[4i,14] In
our approach,[14] a designer borane catalyst was used with
a tempered Lewis acidity and a special steric, size-exclusion[15]
design. This catalyst could alleviate not only some of the key
restrictions of FLP chemistry, but also allowed to expand the
functional group tolerance upon carbonyl reduction. Most
[*] M. Bakos, Dr. ꢀ. Gyçmçre, Dr. A. Domjꢁn, Dr. T. Soꢂs
Research Centre for Natural Sciences
Hungarian Academy of Sciences
Institute of Organic Chemistry
Magyar tudꢂsok kçrffltja 2, 1117 Budapest (Hungary)
E-mail: soos.tibor@ttk.mta.hu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201700231.
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recently, the reach of an FLP carbonyl reduction was
enhanced further to include the deoxygenation of the
arylketones to appropriate alkenes or alkanes.[4i,7e,13b] Nota-
bly, in those tandem reactions no ether formation was
reported. Thus the challenge of performing FLP reductive
etherification is to identify an appropriate catalyst that can
overcome substrate/product inhibition, suppress deoxygena-
tion pathways, and enable catalytic ether bond formation.
Given the improved functional group tolerance of FLPs
with the size-exclusion design, we selected to explore this type
of catalysts for metal-free reductive etherification. It was
envisioned that these FLPs would have the ability to
reversibly “turn on” Brønsted acid catalysis beside FLP
hydrogenation (Figure 1). So, the combined action of the
catalyst 1a in THF under 20 bar H2 pressure. Accordingly, the
FLP catalyst 1a/THF was not inhibited by the products (e.g.
MeOH or ether 3a) and the catalyst was found to be
amenable to selectively promote the reduction, as no over-
reduction occurred.[19] Employing more challenging sub-
strates, such as acetal 2b and ketal 2c, a survey of Lewis
basic ether solvents and Lewis acid components 1a,b was
conducted. This revealed that all of these FLPs could reduce
the substrates selectively and there were only slight differ-
ences in the conversions (see the Supporting Information).
Nevertheless, Lewis acid 1b proved to be more efficient than
1a, thus 1b was selected for subsequent reductions.
With an optimized set of conditions in hand, the scope of
the reaction was investigated as shown in Table 1. Gratify-
ingly, the reaction exhibited broad substrate scope, a variety
Table 1: FLP reduction of acetals to ethers.
Figure 1. Proposed mechanism for FLP mediated reductive etherifica-
tion.
appropriate Lewis acid and a weakly basic oxygen-based
Lewis base on H2, R-OH or H2O would reversibly generate
a strong Brønsted acid.[16,17] This in situ generated acid then
can promote the formation of acetals or ketals from aldehydes
and ketones or other transacetalization process. Finally,
acetals and ketals can be reduced by the FLP generated
borohydride.
The envisioned reductive etherification process would
utilize the same FLP catalyst in a multistep sequence,
however, there were uncertainties concerning how the FLP
catalyst operates in those steps. These include such funda-
mental questions as the reactivity of the FLP catalyst, its
selectivity and inhibition by any intermediates or products.
For these reasons, the feasibility of critical steps of the cascade
reaction had to be investigated involving a) FLP reduction of
acetals and ketals to ethers, b) FLP-mediated acetal forma-
tion. The viability of transformation “b” was far less
questionable, as this type of reaction has been demonstrated
with several Brønsted or Lewis acid catalysts.[18] However, the
catalytic FLP hydrogenation of acetals and ketals has not
been reported in literature, only some side-reactions served as
a possible hint.[13b,14] Thus, we first sought to establish whether
an FLP catalyst could promote reductive cleavage of acetals
and ketals.
[a] Reaction conditions: 20 bar H2 pressure, THF (1.25 mL), 1b
(0.1 mmol), 2 (1.0 mmol), 558C, 12 h. [b] Conversion to ether, deter-
mined by 1H NMR and reinforced by GC-MS. [c] 20 bar H2 pressure, THF
(0.7 mL), B(C6F5)3 (1c, 0.05 mmol), 2a (0.5 mmol), 558C, 16 h.
[d] 50 bar H2 pressure, 1,4-dioxane (1.0 mL), B(C6F5)3 (1c, 0.025–
0.05 mmol), 2a (0.5 mmol), 1008C, 16 h. [e] 808C, 48 h. [f] 558C, 84 h.
[g] 558C, 48 h. [h] 808C, 72 h. [i] Reaction was carried out in [D8]THF.
of electron-deficient and electron-rich aromatic acetals
underwent selective hydrogenation. Importantly, a range of
functionality was tolerated such as nitro, halogen, non-
activated olefin and ester (3b, 3g,h, 3n–q). In addition to
aromatic acetals, reductive etherification of ketals and
aliphatic acetals was also examined (2c, 2i–m). We found
that these substrates could be converted to corresponding
ethers, but more forcing conditions had to be employed for
sterically demanding substrates and what is more, the pivaloyl
derivative 2l proved to be an unsuitable substrate for this
protocol at 558C. Therefore, elevated temperature (808C)
was needed to promote the formation of 3l. One of the most
The catalytic FLP reduction of acetals was examined using
benzaldehyde dimethyl acetal (2a) as substrate, along with
catalyst 1a/THF. To our delight, acetal 2a could be reduced to
benzyl methyl ether (3a) with full conversion using 10 mol%
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Table 2: Tandem reductive etherification of carbonyl compounds with
FLP catalyst.
striking features of this methodology was that it displayed
a high chemo- and regioselectivity. For example, cyclohex-
anone ketal 2m was reduced to cis-ether 3m, a,b-unsaturated
acetals 2n was transformed to allyl ether 3n because of the
steric demand of the reducing agent [Ar3B-H]À. The prepa-
ration of such asymmetrically substituted ethers has been
traditionally performed via multistep reaction, but in many
cases, the access to some of them is sluggish or even
unworkable (e.g. 3m). Interestingly, no side reactions were
detected (according to the 1H NMR and GC-MS experi-
ments) in the reduction of allyl and homoallyl acetals 2o–q.
Thus, an important insight can be distilled from these
reactions concerning the timing of bond breaking and bond
making. The FLP reduction of acetals and ketals seems to be
synchronous, “SN2-like”, as side reactions (e.g. oxonia-Cope
or Prins reaction)[20] of the presumed oxocarbenium ion with
the olefins were not observed. Finally, we evaluated the
archetypal FLP catalyst B(C6F5)3 (1c) for acetal reduction.
We found that this catalyst could deliver the ether product
from 2a (see the Supporting Information). Nevertheless,
a more forcing condition was needed (50 bar, 1008C, 1,4
dioxane) that might be the result of product inhibition.
Subjecting a more challenging and functionalized substrate
2n to the optimized reaction condition, however, resulted in
the decomposition of the staring material, and desired ether
3n was only a minor product. Accordingly, catalyst 1b seems
to be a more general catalyst for FLP reduction of acetals.
With respect to the practical convenience of catalyst 1b,
all of these reactions were set up in open air, using technical
grade solvents without relying on Schlenk or glove box
techniques. While conversions were high, the isolation was
often hampered by the volatility of the products.
Given the success of FLP hydrogenation of acetals to
ethers, we aimed to improve further the practicality of the
protocol. We were intrigued by the possibility to interweave
two catalytic cycles for the construction of ethers, the FLP
hydrogenation of acetals and the FLP-assisted Brønsted acid
catalyzed acetal formation of aldehydes and ketones with
different orthoesters or alcohols. Accordingly, we hoped that
the prior formation of acetals can be circumvented and the
method would enable the one-pot ether formation from
aldehydes or ketones.
Thus, we probed commercially available orthoesters as
alkylating agent (Table 2, entries 1–14). Gratifyingly, these
experiments confirmed that the two FLP mediated catalytic
cycles could be successfully converged, as this protocol
afforded the desired ethers with good yields in technical
grade THF. The background reduction of aldehydes or
ketones to alcohols was mostly negligible, thus the rate of
acetal formation seems to be significantly faster than the FLP
reduction of carbonyls. As anticipated, this method had the
same selectivity as the direct FLP reduction of acetals and
ketals. Accordingly, the process tolerated many functional
groups that are often prone to reduction or inhibit the Lewis
acid. (3m,n, 3r–u). Even the common vanillin ether motifs,
used in fragrance industry, could be synthesized in this
reaction. Industrially relevant preparation of such compounds
usually commences with the appropriate benzaldehydes and
employs a multi-step protocol.[21] Notably, the FLP approach
[a] Reaction conditions: 20 bar H2 pressure, THF (1.25 mL), 1b
(0.1 mmol), 4 (1.0 mmol), orthoformate (3.0 mmol), 558C, 48 h.
[b] Conversion to ether determined by 1H NMR and reinforced by GC-
MS. [c] 20 bar H2 pressure, THF (0.7 mL), B(C6F5)3 (0.05 mmol), 2a
(0.5 mmol), orthoformate (1.5 mmol) 558C, 40 h. [d] 50 bar H2 pressure,
1,4-dioxane (1.0 mL), B(C6F5)3 (0.05 mmol), 2a (0.5 mmol), orthofor-
mate (1.5 mmol) 1008C, 40 h. [e] 558C, 84 h. [f] 808C, 48 h. [g] 808C,
60 h. [h] 808C, 72 h. [i] Conversion of the starting material, formation of
product mixture was detected. [j] 558C, 16 h. [k] Conversion and isolated
yield for toluene product. [l] 20 bar H2 pressure, alcohol (1.25 mL iPrOH/
tBuOH), 808C, 1b (0.1 mmol), 4 (1.0 mmol), 72 h, 3 Š molecular sieves.
[m] 20 bar H2 pressure, iPrOH (1.25 mL), 808C, B(C6F5)3 (0.05 mmol),
4a (0.5 mmol), 72 h, 4 Š molecular sieves. [n] 20 bar H2 pressure,
alcohol (1.25 mL), 558C, 1b (0.1 mmol), 4v (1.0 mmol), 72 h, 3 Š
molecular sieves.
can streamline the synthetic route to ethers from vanillin (4v),
ethylvanillin (4w) and 3,4-dimethoxybenzaldehyde (4z). It is
worth mentioning that we observed the over-reduction of the
electron-rich vanillin ethers at elevated temperature (808C),
as the only products were toluene derivatives 5v,w. Finally, we
demonstrated that it is essential to select the appropriate
Lewis acid for FLP reductive etherification. When the
archetypal tris(pentafluorophenyl) borane (1c) was
employed, at milder condition the tandem reaction halted at
the level of acetal and no or a scant formation of ether was
observed, only more forcing condition could deliver 3a
(Table 2, entries 1, 3).
Our subsequent effort was to find a more accessible
alkylating agent than orthoformates to extend further the
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utility of tandem FLP reductive etherification. It was
expected that the direct treatment of aldehydes and ketones
with alcohols in the presence of size-exclusion FLP catalyst
would also result in the formation of acetal and ketal. Since
the acetal formation is reversible, the equilibrium of acetal or
ketal formations were shifted by the employment of large
excess of alcohols. We used benzaldehyde (4a) and p-
anisaldehyde (4d) to investigate the direct reductive coupling
of carbonyls with alcohols (Table 2, entries 15–18). As
exemplified, secondary or even tertiary alcohols could be
used for unsymmetrical ether formation. While the yield was
modest because of the competing FLP reduction of aldehyde
4d to alcohol, the impressive feat of this approach was its
convenience. Although the ketal formation is more difficult,
presumably for steric reason, the direct reductive etherifica-
tion of 4-(tert-butyl)cyclohexan-1-one (4m) with isopropanol
was still possible. Nevertheless, carbonyl reduction outper-
formed ether formation (6m). Finally, in a similar, but a more
selective manner ethyl vanillin (4w) could be transformed to
isopropylether 6w.
synthetically inconvenient or even intractable to access by
alternative synthetic strategies. The experimental ease of this
methodology is also worth emphasizing as all of these
reactions were set up in open air, using technical grade
solvents without relying on Schlenk techniques. Conceptually,
the reversible FLP-assisted Brønsted acid catalysis can be
considered as an on-demand acid catalysis. In this context, the
outlined FLP cascade catalysis might establish a starting point
for further work in this area. Studies to extend the FLP
concept is underway in our laboratory and will be reported in
due course.
Acknowledgements
We are grateful for the financial support from OTKA
(K116150). The authors thank Gedeon Richter Plc. and
ꢁgnes Gçmçry for the HRMS measurements, and Judith
Mihꢂly for IR measurements.
With these FLP mediated reductive etherification meth-
ods established, previous findings[18,22] in oxocarbenium
chemistry caused us to further question whether the applied
Lewis acid catalyst 1b might also contribute to the trans-
acetalization process or even outperform the presumed FLP-
assisted Brønsted acid catalysis (Figure 2). This hypothesis
Conflict of interest
The authors declare no conflict of interest.
Keywords: boranes · catalysis · frustrated Lewis pairs ·
hydrogenation · reductive etherification
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scope, functional group tolerance and selectivity. This FLP-
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enables the synthesis of various ethers that would be either
4
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acidic borane 1a with size-exclusion design forms a kinetically
labile complex in THF with benzyl-alcohol and H2O, see
ref. [14].
[18] Methoden der Organischen Chemie, O/O- und O/S-Acetale
(Eds.: H. Hagemann, D. Klamann), Thieme, Stuttgart, 1991,
pp. 133 – 302.
[19] B(C6F5)3-catalyzed reduction of alcohols and cleavage of aryl
and alkyl ethers with silane was reported: V. Gevorgyan, M.
Rubin, S. Benson, J.-X. Liu, Y. Yamamoto, J. Org. Chem. 2000,
65, 6179 – 6186.
[20] Selected examples for related oxonia-Cope and Prins reactions:
a) S. R. Crosby, J. R. Harding, C. D. King, G. D. Parker, C. L.
Willis, Org. Lett. 2002, 4, 577 – 580; b) R. Jasti, S. D. Rychnovsky,
J. Am. Chem. Soc. 2006, 128, 13640 – 13648; c) G.-Q. Liu, B. Cui,
R. Xu, Y.-M. Li, J. Org. Chem. 2016, 81, 5144 – 5161.
[21] P. A. Ochsner (Givaudan Corp.), US 4657700 A, 1987.
[22] As Yoon suggested, electron-deficient decaborane or decom-
posed decaborane can act as catalyst for the formation of acetal
and the generation of oxonium ion in decaborane mediated
reductive etherification of aromatic aldehydes, see ref. [9e].
[10] For selected examples of reductive etherification using H2 as
reducing agent, see: a) N. Kalutharage, C. S. Yi, J. Am. Chem.
Soc. 2015, 137, 11105 – 11114; b) N. Kalutharage, C. S. Yi, Org.
Lett. 2015, 17, 1778 – 1781; c) L. J. Gooßen, C. Linder, Synlett
2006, 3489 – 3491.
[11] A. Williamson, Justus Liebigs Ann. Chem. 1851, 77, 37 – 49.
[12] For reports on ether formation by dehydration, see a) A. Corma,
M. Renz, Angew. Chem. Int. Ed. 2007, 46, 298 – 300; Angew.
Chem. 2007, 119, 302 – 304; b) W. K. Gray, F. R. Smail, M. G.
Hitzler, S. K. Ross, M. Poliakoff, J. Am. Chem. Soc. 1999, 121,
10711 – 10718.
Manuscript received: January 9, 2017
Revised: February 10, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Frustrated Lewis Pairs
Double success: A metal-free reductive
etherification method using frustrated-
Lewis-pair-promoted reduction reactions
of carbonyl compounds was developed.
The key to success was the deliberate
application of recently discovered water-
tolerant frustrated Lewis pairs. The
developments can be viewed as a double
success in FLP catalysis and formation of
ether bonds.
M. Bakos, ꢁ. Gyçmçre, A. Domjꢂn,
T. Soꢃs*
&&&& — &&&&
Auto-Tandem Catalysis with Frustrated
Lewis Pairs for Reductive Etherification of
Aldehydes and Ketones
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!