Ether formation through reductive coupling of ketones or aldehydes catalyzed by a mesoionic carbene iridium complex

Article abstract of DOI:10.1039/c7cy01832k

An iridium(iii) Cp? complex containing a triazolylidene-pyridyl C,N-bidentate-coordinating ligand is a very powerful catalyst for the transformation of ketones and aldehydes into symmetrical ethers. This highly efficient reductive coupling proceeds immediately at room temperature and at a low catalyst loading (0.1 mol%) when Ph₂SiH₂ is used as an additive. Aromatic carbonyl substrates react faster than aliphatic ketones or aldehydes, and the substrate scope suggests some functional group tolerance. Likewise, the condensation of alcohols to symmetrical ethers is catalyzed by this triazolylidene iridium complex, though ether formation is an order of magnitude slower than when starting from the analogous ketone or aldehyde as a substrate, suggesting that alcohols are not potential intermediates in the reductive coupling process. Prolonged reactions or modification of the silane additive lead to ether cleavage and dehydration, thus affording the corresponding olefin. Mechanistic insights and in particular the different reactivities of alcohols and ketones have been exploited to develop a synthetic methodology for the iridium-catalyzed formation of unsymmetrical methyl ethers (R-OMe) in good yields.

Full text of DOI:10.1039/c7cy01832k

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PAPER
Qingzhu Zhang et al.
Catalytic mechanism of C–F bond cleavage: insights from QM/MM
analysis of fluoroacetate dehalogenase
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DOI: 10.1039/C7CY01832K
Catalysis Science & Technology
ARTICLE
Ether formation through reductive coupling of ketones or
aldehydes catalysed by a mesoionic carbene iridium complex
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
,a,b
A. Petronilho, A. Vivancos and M. Albrecht*
DOI: 10.1039/x0xx00000x
An iridium(III) Cp* complex containing a triazolylidene-pyridyl C,N-bidentate coordinating ligand is a very powerful catalyst
for the transformation of ketones and aldehydes to symmetrical ethers. This reductive coupling proceeds highly efficiently
www.rsc.org/
2 2
already at room temperature and at low catalyst loading (0.1 mol%) when Ph SiH is used as an additive. Aromatic
carbonyl substrates react faster than aliphatic ketones or aldehydes, and a substrate scope suggests some functional
group tolerance. Likewise, the condensation of alcohols to symmetrical ethers is catalyzed by this triazolylidene iridium
complex, though ether formation is an order of magnitude slower than when starting from the analogous ketone or
aldehyde as substrate, suggesting alcohols are not potential intermediates in the reductive coupling process. Prolonged
reactions or modification of the silane additive lead to ether cleavage and dehydration, thus affording the corresponding
olefin. Mechanistic insights and in particular the different reactivity of alcohols and ketones has been exploited to develop
a synthetic methodology for the iridium-catalyzed formation of unsymmetrical methylethers (R–OMe) in good yields.
reaction trajectories is critical for the selective transformation
of alcohols to afford either ketones (Eq. 1), or (un)symmetrical
ethers (Eq. 2), or olefins and alkanes through formal
Introduction
The ether linkage is one of the most abundant functional
groups in pharmaceuticals and bulk material, and classically
formed through Williamson synthesis or acid-catalyzed
11
dehydration and deoxygenation (Eq. 3), respectively. All of
these processes have obvious implication for biomass
12
1
conversion.
condensation of alcohols. However these methodologies have
severe limitations such as the harsh reaction conditions, the
(
over)stoichiometric use of acid or base, the formation of
2
significant side products and a limited scope. Recent efforts
concentrated on catalytic methods under milder conditions,
including in particular O–H bond activation and dehydration
reactions. Ubiquitous precursors are alcohols or carbonyl
3
4
Enhanced selectivity towards ethers and ketones has been
5
successfully achieved when using late transition metals such as
compounds, which upon formal elimination of one equivalent
13,14
palladium or iridium.
Elegant work on an N-heterocyclic
of H O may condense to ethers. Generally, water is trapped
2
carbene iridium complex indeed indicated that this type of
complexes constitutes an interesting class of catalyst for
etherification reactions, as relatively short reaction times (3–6
h) produced high quantities of ether products from a variety of
alcohols, even though elevated temperatures (110 °C) were
6
7
8
with Lewis acids such as zinc(II), indium(III), or silyltriflates.
The utilization of silanes as additives has demonstrated a
positive effect through formation of siloxane products.
8
,9
Typical reaction times (4–24 h) and catalyst loadings (5–20
mol%) are rather high, however, for these processes to
become mechanistically and operatively attractive.
14
needed.
We have recently reported that similar iridium(III)
complexes containing ylidic C-donor ligands rather than an
Previous work on rhenium oxides allowed for decreasing
10
the catalyst loading to 1 mol%. These complexes catalyze
both dehydration to ethers or olefins and (de)hydrogenation
of alcohols in a competitive process, and controlling these
15
Arduengo-type carbene, viz complexes 1–3, are catalytically
16
active in the hydrosilylation of ketones and aldehydes at low
17
catalyst loadings (< 0.1 mol%; Scheme 1). We now report that
complex
1 with a triazolylidene ligand also catalyzes
dehydration, which provides an efficient and clean access to
ethers under mild reaction conditions (RT, reaction times min
to h). Switching of the reaction conditions (silane,
temperature, substrate) allows for favoring either formation of
the ether or the hydrosilylation product, or to induce formal
oxygen elimination, identifying complex
1 as a multitasking
catalyst that completes all reactions from Eq. 1–3.
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respectively, catalyze exclusively the hydrosilylation of the
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DOI: 10.1039/C7CY01832K
ketone when used under the same reaction conditions (Table
1
, entries 2 and 3). The reactivity of complex 1 is
complementary to these systems, and hydrosilylation is
entirely suppressed. In contrast, the carbene-free iridium
precursor complex [Cp*IrCl2]2 is essentially inactive under
these conditions and no ketone conversion was observed after
1
5 min. Marginal conversions were only noted after prolonged
reaction times (15% after 24 h; entry 4), with the
hydrosilylation as the major pathway, and only traces of
dibenzyl ether were formed. No conversion was observed in
, which reach the absence of an iridium complex (entry 5). These
Scheme 1 Catalytic hydrosilylation with complexes
about 10,000 turnovers.
1
3
experiments emphasize the relevance of the iridium center
and the carbenic ligands for promoting substrate activation
and the specific role of the triazolylidene ligand. The diverging
reactivity of
availability of a nitrogen lone pair in the triazolylidene system
, and in other parts perhaps a consequence of the
catalyzes the hydrosilylation of acetophenone when electrophilic character of the triazolylidene and the ensuing
1 and 2 is presumably associated in parts with the
Results and discussion
Etherification of ketones. While the triazolylidene iridium of
complex
Et SiH is used as silylating agent, symmetric dibenzyl ethers enhanced reactivity towards hydrides, while the imidazole-
1
1
1
7
3
17
are formed when the Si–H source is changed to Ph SiH2 derived heterocycle in
2
demonstrates nucleophilic behavior.
Scheme 2). This transformation constitutes an overall Likewise, a bipyridyl-ligated iridium Cp* analogue was
reductive condensation of two ketones with H O as a formal reported to require acids to catalyze etherification and is
2
(
2
1
9
side product.
inactive on its own.
Thus, when diphenylsilane was added to a mixture
Conversions and reaction rates for ether formation are
containing 4-fluoroacetophenone and complex
1
(1 mol%), strongly dependent on the type of silane additive used and on
immediate gas evolution was noted. Analysis of the reaction the catalyst loading. While formation of the dibenzyl ether
I
is
1
mixture by H NMR spectroscopy after 5 minutes revealed complete within 5 min when 2 equiv Ph SiH are used, Et SiH
2
2
3
complete consumption of the starting material and the (2 equiv) only gave the hydrosilylation product II. Increasing
selective formation of the substituted and symmetrical the amount of Et SiH to 4 molequiv. induced ether formation,
3
dibenzyl ether I (R = 4-F) as a 1:1 mixture of the rac- and meso- however the selectivity is poor with only 26% ether
I and 74%
isomers, indicated by two quartets at H 4.48 and 4.18, and silylether II after 15 min (entry 6). The conversion does not
two doublets for the methyl groups at H 1.43 and 1.34 (CDCl3 increase significantly when extending the reaction time to 1 h.
1
3
solution). The C NMR spectrum shows diagnostic signals at
7

Likewise, an increase of Ph SiH to 6 equivalents reduced the
2 2
selectivity towards ether I, and instead, significant quantities
C
8
1
4.1, 73.9 and 23.1, 24.7, further confirming ether formation.
Moreover, gas formation is due to the evolution of H , which of 4-fluoro-styrene (17%) and 1-ethyl-4-fluorobenzene (18%)
2
1
was unambiguously identified by a singlet at H 4.62 in the H were formed as side products due to dehydration and
NMR spectrum.
hydrogenation of the reduced ketone (entry 7). In contrast,
phenylsilane increases the reaction rate and full conversion
with complete selectivity towards the ether product
observed within 5 min even when using only 1.4 equiv. PhSiH3
entry 8).
Etherification is also accomplished with lower catalyst
I was
(
loadings. With 0.1% loading of 1, full conversion of 4-
fluoroacetophenone is achieved in minutes and the exquisite
selectivity towards the ether product
I remains preserved
(
entry 9). This performance indicates a turnover frequency in
–
1
excess of 12,000 h . Further lowering of the iridium
concentration to 0.05% compromises product selectivity.
While the ketone is fully converted again in minutes, a product
mixture resulting from competitive hydrosilylation and
etherification was obtained together with products from
elimination (styrene and ethylbenzene; entry 10).
Scheme 2 Diverging silane-dependent reactivity of acetophenone
derivatives with complex
1 as catalyst precursor.
Under these conditions, the maximum yield of the ether
The reductive dibenzyl ether formation is specific to
complex . The related complexes and containing a
mesoionic imidazolylidene and an ylidic C-donor ligand,
product
I did not exceed 44% even when extending the
1
2
3
reaction time to 5 h. Longer reaction times were not
advantageous as only the quantities of elimination products
2
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raised (aggregated 31% after 5 h vs 22% after 1 h). The product on the aromatic ring. For example, 4-fluoro-acetophVeienwoAnreticliesOfnulilnlye
redistribution from the ether
and the silylether II to the and exclusively converted to the ether prodDuOctI:(1e0n.1t0ry392/)C,7wCYh0il1e83th2Ke
deoxygenated products suggests that complex is also parent acetophenone produces a 1:2 mixture of I and II because of
competent in the catalytic cleavage of ethers to form competitive etherification and hydrosilylation (entry 1). A methoxy
I
1
dehydrated olefins and alkanes.
Table 1 Reactivity of 4-fluoroacetophenone with different iridium complexes and silanes.
group in para position (entry 3) induced rapid conversion, though
a)
entry
1
complex
loading
1%
silane (equiv)
Ph SiH (2 eq)
time
conversion
yield of I
99%
1
5 min
99%
2
2
b)
2
3
4
5
6
7
8
9
2
1%
1%
Ph SiH (2 eq)
5 min
5 min
24 h
99%
99%
15%
<1%
2
2
b)
3
Ph SiH (2 eq)
<1%
2
2
[Cp*IrCl2]2
1%
Ph SiH (2 eq)
<1%
<1%
26%
2
2
---
1
---
Ph SiH (2 eq)
24 h
<1%
2
2
1%
Et SiH (4 eq)
3
15 min
5 min
5 min
5 min
5 min
99%
99%
99%
99%
c)
1
1%
Ph SiH (6 eq)
65%
2
2
1
1%
PhSiH (1.4 eq)
99%
99%
29%
44%
40%
3
1
0.1%
0.05%
Ph SiH (2 eq)
2
2
10
1
Ph SiH (2 eq)
97%
99%
99%
28%
2
2
d)
1
5
h
h
e)
b)
11
1
0.02%
Ph SiH (2 eq)
5 min
<1%
2
2
1
5
h
h
85%
88%
27%
28%
a)
b)
General conditions: iridium complex, 4-fluoroaaliphacetophenone (0.5 mmol), Ph SiH (185 L, 1 mmol), CH Cl (1 mL), RT.
2
2
2
2
c)
d)
Conversion exclusively to the silylether product II. side products 4-fluorostyrene (17%) and 1-ethyl-4-fluorobenzene (18%). side
products: silylether II (34%), 4-fluorostyrene (13%) and 1-ethyl-4-fluorobenzene (9%).
e)
side products: silylether II (29%), 4-
fluorostyrene (17%) and 1-ethyl-4-fluorobenzene (14%).
Lowering the loading of complex
1 even further to 0.02 mol% the major product arose from dehydration to afford the 4-ethyl-
increased the silylether fraction in the product mixture and led anisole, presumably via intermediate formation of the substituted
to incomplete ketone consumption even after 5 h (entry 11), dibenzyl ether (see also below). Variation of one of the substituents
suggesting a limited activity of complex
concentrations. Moreover, the fairly constant ratio of ether
1
at such dilute at the carbonyl group is readily tolerated. For example, ketones
with two aryl substituents such as benzophenone reacted smoothly
I
and silylether II at extended reaction times suggests that the and gave the ether product exclusively (entry 4), and likewise,
etherification and hydrosilylation are competing pathways substituted benzaldehydes afforded the correspondingly
rather than consecutive reactions. Overall, the activity of substituted dibenzyl ether as the predominant or even exclusive
complex
and turnover frequencies in excess of 12,000 h under optimal were transformed in about equal rate as the unsubstituted
conditions (0.1 mol% loading). substrates (entries 6,7). Obviously, the direct dehydration pathways
1 is substantial with turnover numbers around 1000 product (entry 5). Methoxy- or fluoro-substituted benzaldehyde
–
1
Substrate Scope. The scope of the etherification was evaluated observed for ketones
with a series of aromatic and aliphatic ketones and aldehydes that lead to styrene and alkane derivatives are suppressed in such
(
Table 2). For benzylic aldehydes and ketones, conversions generally substrates. Of note, the product selectivity was not affected by the
reached completion within as little as 5 min, though selectivity to
the dibenzyl ether product varied significantly with the substituents
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groups), and the catalysis was selectively producing the
hydrosilylation product, and no traces of the dibenzyl ether were
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Table 2 Catalytic activity of complex 1 with aromatic ketones and
aldehydes.
a)
detected. Based on the high stability of complex 1 in an acidic
17,20
environment,
we surmise that the acidic functional groups
b)
interfere with a iridium hydride species that is transiently formed in
entry
1
substrate
conv’n Major product
Yield I/II
2
1
a putative catalytic cycle, thus suppressing any ketone insertion
22
and substrate conversion.
99%
30%/65%
The complete reduction of the ketone 4-methoxy-
acetophenone to 4-ethylanisole (cf Table 2, entry 3) deserves some
further comments. While the reactivity of this substrate at RT is too
high to detect any intermediate products, alteration of the reaction
temperature or the substrate ketone decelerates the reaction and
allows intermediates to be identified. For example, related
reactivity patterns were observed with 4-fluoroacetophenone in the
presence of diphenylsilane upon prolonged reaction times. Thus,
leaving the reaction for 30 instead of 5 min induced a decrease of
the dibenzyl ether product I (cf Table 1) and instead accumulation
of para-fluorostyrene was observed. Time-dependent analysis of
the reaction mixture indicates that styrene formation is due to
dehydration of the dibenzylether. Further reaction led to styrene
hydrogenation due to the presence of dihydrosilane and complex 1.
Obviously, the methoxy substituent accelerates this sequential
reaction substantially, and hence already after 5 min, the fully
hydrogenated product is the major species. When performing the
reaction with 4-MeO-acetophenone at 0 °C instead of RT, the
reaction mixture after 15 min revealed essentially full conversion of
the starting material and concomitant formation of a 3:1 ratio of
the ether and the dehydrated ethyl anisole (Scheme 3). These two
products are readily identified by the distinct chemical shift of the
OCH3 protons, and by the characteristic doublet and triplet
multiplicity of the C-bound CH3 group at 1.32 and 1.20 ppm,
respectively (ESI). After 30 min, the dehydrated ethyl anisole was
the major component and the exclusive product after 1 h,
supporting a stepwise formation. Likewise, etherification of
benzophenone with 1% catalyst loading is complete in 5 minutes,
and the corresponding ether is the exclusive product at this time.
Monitoring the reaction beyond completion revealed the formation
of diphenylmethane after 1 h as a result of subsequent
transformation of the ether. Overall, these observations suggest
that the formation of deoxygenated products arises from
degradation of the dibenzyl ether. If undesired, this latter process is
readily suppressed by quenching the catalytic reaction with
2
3
99%
99%
90%/--
c)
79% / --
4
5
99%
95%/ --
99%
99%
>95%/ --
d
6
70%/20%
a)
General conditions: complex 1 (5 mol), substrate (5.0 mmol),
b)
Ph SiH (10 mmol), CH Cl (1 mL), RT, 5 min;
yield of I
2
2
2
2,
1
(
dibenzylether) and II (benzylsilyl ether) fromc)
H
NMR
spectroscopy using anisole as internal standard;
dehydrated
d)
product originating from I, see text for details; same ratio after 5
min and after 24 h reaction.
reaction time. Thus, stirring the product mixture obtained from
ortho-methoxybenzaldehyde, silane, and complex 1 for 24 h rather
than 5 min (entry 6) afforded the same 7:2 product selectivity.
The catalyst tolerates a set of functional groups including aryl
halides (entry 2), and ethers (entries 3,6). However, bromides gave
a mixture of compounds. The scope and limitation of the functional
group tolerance was further evaluated by running catalytic
experiments with fluoro-acetophenone (entry 2) as the substrate in
the presence of stoichiometric quantities of methyl benzoate,
2
3
pentane. These reactivity patterns demonstrate the unique
activity of the triazolylidene iridium complex 1 in efficiently
catalyzing multiple transformations including hydrosilylation,
benzoic acid, phenol, and aniline (SI, Table S1). These etherification, and deoxygenation processes. Toggling between
measurements indicate that the ester group is not affecting the rate these transformations is straightforward by rigorous control of the
or selectivity of ether formation. However, acidic protons had a reaction conditions.
marked influence. Phenol reduced the conversion rate and 15
rather than 5 min were required to reach full conversion of the
ketone. More significantly, the selectivity dropped markedly and
the ether was formed in only 30% with the silylether II as the main
product (70%). Carboxylic acid and primary amine groups reduced
the activity significantly (less than 20% conversion after 5 min
compared to full conversion in the absence of these functional
4
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Scheme
4
Etherification of 4-fluoro- -methylbenzyl alcohol with
diphenylsilane and 1.
A brief scope of the etherification from alcohols (Table 3) reveals
a similar reaction trend as observed for ketone etherification (cf
Table 2). For example, conversions depend on the para aryl
substituent of secondary benzylalcohols and is following the MeO >
F > H trend (entries 1–3 in Table 3). Interestingly, while the product
from ketone etherification is not stable and afforded the
substituted ethylbenzene upon prolonged reaction time (cf Scheme
Scheme
3 Reactivity of arylketones upon prolonged reaction time,
illustrating the multipurpose catalytic activity of complex 1.
The conversion of aliphatic carbonyl compounds was less
selective under similar conditions and hydrosilylation was the
3), such reactivity patterns are suppressed when starting from the
dominant reaction trajectory, both for ketones and aldehydes. The alcohol as substrate and only the ether product is formed. This
preferential conversion of aliphatic aldehydes and ketones to the reactivity pattern provides further support that formal
hydrosilylation product rather than the dialkyl ether may be deoxygenation of the ketone occurs from the ether intermediate,
and not directly from the ketone, and that the etherification of
ketones and alcohols proceeds through distinct pathways.
electronically induced due to the lower Lewis basicity of the
carbonyl oxygen in aliphatic substrates. An increase in catalyst
loading did not improve the selectivity. Likewise, utilization of a
larger excess of silane (up to 6 molequiv.) or sequential addition
does not improve the selectivity. However, replacing Ph SiH with
While diphenylmethanol was cleanly converted to the
symmetrical ether (entry 4), aliphatic substrates and phenols were
unreactive and did not lead to any products, suggesting some
relevance of the –hydrogen in the substrate. Likewise, tertiary
alcohols such as 2-phenyl-2-propanol did not afford the ether
product but instead yielded -methyl styrene through formal
2
2
PhSiH afforded Bu O from butyraldehyde in excellent yield and
3
2
selectivity.
26
elimination of H O (entry 5).
2
Etherification of alcohols. Since complex 1 was previously
17
shown to catalyze the hydrosilylation of ketones, we sought to
probe any relevance of alcohols as intermediates en route to the
formation of the dibenzyl ethers. The role of silyl ethers as potential
intermediates can be excluded based on the the fact that the ratio
of dibenzyl ether I vs silylether II was nearly constant and
independent of reaction times (though dependent on other
parameters such as the silane co-reagent, or the catalyst loading).
We therefore evaluated the reactivity of alcohols with complex 1
under standard conditions (Ph SiH , RT).
a)
Table 3 Catalytic activity of complex 1 with alcohols.
b)
entry
substrate
Major product
Yield
6
7%
99% 1h)
1
(
4
0%
61% 24h)
2
3
2
2
(
When using 4-fluoro-α-methylbenzyl alcohol, i.e the substrate that
results from reduction of fluoroacetophenone (cf Table 1), dibenzyl
etherification is indeed observed (Scheme 4). It should be noted
that higher catalyst loadings were required to achieve substantial
conversions (1 mol% as opposed to 0.1 mol% when starting from
the ketone), and no significant conversion of the alcohol occurred
at 0.1 mol% 1. Even with these higher catalyst loadings, ether
formation was slower and reached only 67% conversion after 5 min
>95%
7
5%
(>95% 0.5
h)
4
5
(
cf full conversion of the ketone in the same time period). As for the
1
conversion of ketones, evolution of H was observed by H NMR
2
spectroscopy, though qualitatively, gas formation was less
2
4
intense. The product selectivity was exclusive, only the substituted
dibenzyl ether was formed without any detectable amounts of
92%
25
silylether. Again, Ph SiH gave higher conversions than Et SiH, (e.g.
2
2
3
8
1% vs 20% in the model reaction in Scheme 4 after 15 min). These
results indicate a similar relevance of the silane on the reaction rate
as observed for ketone etherification.
a)
General conditions: complex 1 (5 mol, 1 mol%), substrate (0.5
mmol), Ph SiH (1 mmol), CH Cl (1 mL), RT, 5 min. R = SiHPh (or H
from silylether hydrolysis); spectroscopic yield using anisole as
internal standard (maximum yield and time in parentheses).
2
2
2
2,
2
b)
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This result excludes the silylether product as an intVeierwmAertdicilaetOenleinne
route to forming the symmetrical ether proDduOcI:t1a0n.1d03v9ic/Ce7vCeYr0s1a8.3A2Kn
alternative pathway involves an iridium-stabilized silylenes
Mechanistic Insights. The reactivity patterns deduced above
suggest a similar activated substrate when starting from either the
ketone or the alcohol. The higher reaction rate when starting from
ketones (5 min for completion with 0.1 mol% iridium), the 10-fold
higher turnover numbers, and the absence of dibenzyl ether
products from substrates that lack an -hydrogen lend support to a
direct conversion of the ketone, while the alcohol may require a
[
Ir]=SiPh2 as active species for the reductive coupling of two
3
2
carbonyl species, though currently we do not have any support for
such a process.
formal hydrogen abstraction to initiate ether formation. Monitoring
1
the catalytic conversion of 4-acetophenone by
H
NMR
spectroscopy revealed the formation of a hydride at  –14.5 ppm,
H
which persists throughout the reaction. Such hydride formation was
also observed in the reaction of complex 1 with Ph SiH with the
2
2
same chemical shift, however any attempts to isolate this species
have been unsuccessful so far. Of note, the chloride analogue of
complex 1 containing an iridium-bound chloride rather than a H O
2
ligand did not react with the silane to form a hydride complex, and
also failed to catalyze the etherification or hydrosilylation, thus Scheme 5 Etherification of 4-fluoroacetophenone (a) and 4-fluoro--
27
pointing to a relevant role of this iridium hydride species.
methylbenzyl alcohol with deuterated diphenylsilane.
However, complexes 2 and 3, which are inactive for etherification,
do also form a hydridic species, hence suggesting that the
triazolylidene heterocycle plays a critical role in ensuing the Synthesis of unsymmetrical ethers. The fact that alcohols in
observed activity, presumably due to the availability of an general and aliphatic alcohols in particular react substantially
unsubstituted nitrogen. An interplay of a hydridic species with a slower than ketones prompted us to extend this methodology to
nitrogen lone pair as (transient) proton scavenger provides a the synthesis of unsymmetrical ethers. Our first attempt focused on
tentative rationale for the observed facile generation of H as a side the preparation of methylethers using methanol as mild and
2
2
8,29
reaction of complex 1 with silane (Scheme S1).
convenient methylating agent (Scheme 6), since methylethers are
Hydrogen itself has no beneficial effect on the ether formation widely abundant as functional entities and protecting groups. When
nor on selectivity aspects. For example, substitution of the silane MeOH was used as solvent, no symmetrical dibenzyl ether was
with H was unproductive and reaction of 4-fluoroacetophenone observed, and the only product formed was the unsymmetrical
2
under standard conditions (0.1 or 1 mol% 1, CH Cl , RT) with 1 atm methyl-benzyl ether. However conversion is unattractively slow and
2
2
H2 did not lead to any etherification nor detectable ketone after 12 hours only 20% of the cross-coupled ether is formed,
30
reduction. Likewise 4-fluoro--methylbenzyl alcohol did not yield presumably because MeOH prevents the stabilization of the iridium
any ether under these conditions. These results further confirm that hydride intermediate. The use of a MeOH:CH Cl solvent mixture
H generation is a process that occurs independently and has no (1:3 v/v) rather than pure MeOH improved the yield of the
2
2
2
implications on the activity of 1 and the etherification process.
To shed further light on the role of hydrogen in the ether 0.1 mol% catalyst loading and upon sequential addition of the silane
formation process, catalytic experiments were performed with in small portions (10  0.2 molequiv Ph SiH , added every 30 min).
deuterated silane, Ph SiD (Scheme 5). When starting from 4- This protocol together with the mixed MeOH:CH Cl solvent gave
unsymmetrical ether substantially. Best results were achieved with
2
2
2
2
2
2
fluoroacetophenone, the deuterated ether I–D2 was formed complete consumption of the starting ketone and showed good
exclusively. This outcome may be expected, since the silane selectivity towards the methyl benzylether product (60%) together
constitutes the only plausible hydrogen source. With the with minor quantities of the symmetrical dibenzylether I (15%).
corresponding alcohol as substrate, no deuterium incorporation
was observed in the ether product. Both reactions were
1
accompanied by significant gas evolution, however H NMR
spectroscopy did not reveal any H2 or HD, thus suggesting
predominant formation of D . Accordingly, hydrogen evolution does
2
not involve the alcohol. Moreover, alcohol dehydrogenation and
formation of the corresponding ketone as a potential intermediate
in the etherification of alcohols is unlikely when considering the MeOH.
distinct isotope incorporation. More plausible may be a mechanism
Scheme 6 Synthesis of unsymmetrical methylether from a ketone and
that involves either
a
substrate activation similar to
dehydrogenative silylation, which has been reported as an efficient Conclusions
methodology to generate silylethers from alcohols, including
A triazolylidene ligand bound to an Ir(Cp*) unit imparts high
catalytic activity and promotes the smooth reductive condensation
of ketones to produce dialkyl ethers under mild conditions. Room
temperature and low catalyst loadings (0.1 mol%) are efficiently
producing the corresponding ether in high yields. Similar reactivities
31
methods involving NHC complexes, as catalyst precursors. In such
a model, the silylether-type intermediate must not be released
from the iridium coordination sphere (Scheme S1), since the
dibenzyl ether vs silylether ratio I:II has been shown to be
essentially constant throughout and after the catalytic reaction.
6
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Catalysis Science & Technology
ARTICLE
portions sequentially each 30 min) was added. AliqViuewotAsrtic(l5e0OnlinLe)
are observed when starting from alcohols, though conversions are
typically slower. This reactivity difference has been exploited to
produce methyl ethers via the selective reductive coupling of a
ketone with MeOH. Such mild procedures add to the already vast
reactivity portfolio of ketones, providing a new approach to
introduce an ether functionality into complex molecules. A current
focus of our work in this area is directed towards increasing the
scope and functional group tolerance to enhance the utility of this
new method for producing pharmaceutically relevant
intermediates.
were transferred into an NMR tube containing CDCl (0.6 mL) and
DOI: 10.10 33 9/C7CY01832K
the reaction progress was monitored by H NMR spectroscopy.
1
Acknowledgements
We thank the European Research Council (ERC CoG 615653)
and Science Foundation Ireland (SSPC, 12/RC/2275) for
financial support.
An attractive prospect of the catalytic procedure introduced here is
the fact that the conditions can be modified in such a way that the
triazolylidene iridium complex catalyzes the conversion of carbonyl
substrates in three different directions, forming either alcohols
through hydrosilylation, or ethers through reductive coupling, or
olefins through a dehydration pathway. The use of different silanes,
reaction times, and temperatures allows to direct product
formation towards either of these three product classes from one
single substrate. Such type of promiscuity of a catalyst is highly
desirable and may provide a direct access to cascade processes and
tandem transformations with one single catalytic system. Of note,
related complexes containing an imidazole-derived carbene ligand
are only active in one of these three reactions (viz hydrosilylation),
thus underpinning the unique features of triazolylidenes as
spectator ligands and their expanded scope in catalysis.
Notes and references
1
a) A. Williamson, Philos. Mag. 1850, 37, 350; b) R. H. Clark,
W. E. Graham and A. G. Winter, J. Am. Chem. Soc. 1925, 47
,
,
,
2
3
3
748; c) M. P. Doyle and C. T. West, J. Org. Chem. 1975, 40
821; d) M. P. Doyle and C. T. West, J. Org. Chem. 1975, 40
829; e) A. Corma and M. Renz, Angew. Chem. Int. Ed. 2007,
46, 298.
2
3
a) O. C. Dermer, Chem. Rev. 1934, 14, 385; b) S. V. Ley and A.
W. Thomas, Angew. Chem. Int. Ed. 2003, 42, 5400.
a) L. V. Desai, K. L. Hull and M. S. Sanford, J. Am. Chem. Soc.
2
004, 126, 9542; b) T. Shintou and T. Mukaiyama, J. Am.
Chem. Soc. 2004, 126, 7359. For reviews, see: c) S. Enthaler
and A. Company, Chem. Soc. Rev. 2011, 40, 4912; d) S. R.
Neufeldt and M. S. Sanford, Acc. Chem. Res. 2012, 45, 936.
For leading reviews, see: a) J. F. Hartwig, Acc. Chem. Res.
4
1
3
2
998, 31, 852; b) J. F. Hartwig, Angew. Chem. Int. Ed. 1998,
, 2046; c) A. R. Muci and S. L. Buchwald, Top. Curr. Chem.
002, 219, 131. For selected examples, see: d) P. C. Young, N.
7
A. Schopf and A.-L. Lee, Chem. Commun. 2013, 49, 4262; e) S.
Ueno and J. F. Hartwig, Angew. Chem. Int. Ed. 2008, 47
Experimental
General
,
1
2
928; f) M. Roggen and E. M. Carreira, Angew. Chem. Int. Ed.
011, 50, 5568; g) K. J. Kilpin, U. S. D. Paul, A.-L. Lee and J. D.
Complexes 171a –4 were synthesized according to literature
procedures. All other reagents are commercially available and
were used as received. Unless specified otherwise, NMR spectra
were recorded at 25 ºC on Varian Innova spectrometers operating
at 300, 400, or 500 MHz ( H NMR) and 75, 100, or 125 MHz ( C{ H}
NMR), respectively. Chemical shifts were referenced to residual
Crowley, Chem. Commun. 2011, 47, 328; h) H. Faustino, I.
Varela, J. L. Mascarenas and F. Lopez, Chem. Sci. 2015, 6,
2903.
5
6
7
E. Arceo, J. A. Ellman and R. G. Bergman, J. Am. Chem. Soc.
2010, 132, 11408.
1
13
1
S. Kim, K. Nam Chung and S. Yang, J. Org Chem. 1987, 52
,
solvent resonances or SiMe . Assignments are based on homo- and
heteronuclear shift correlation spectroscopy.
3917.
4
T. Mineno, R. Tsukagoshi, T. Iijima, K. Watanabe, H.
Miyashita and H. Yoshimitsu, Tetrahedron Lett. 2014, 55
765.
,
General procedure for the etherification of ketones and aldehydes
In a representative procedure, 4-fluoro-acetophenone (600 L, 5.0
mmol) was added to a solution of CD Cl (1 mL) containing complex
3
8
9
M. B. Sassaman, K. D. Kotian, G. K. S. Prakash and G. A. Olah,
J. Org. Chem. 1987, 52, 4314.
2
2
1
(4.0 mg, 5.0 mol) and stirred for 5 min. Then Ph SiH (1.90 mL,
2 2
a) N. Sakai, Y. Nonomura, R. Ikeda and T. Konakahara, Chem.
Lett. 2013, 42, 489; b) N. Sakai, K. Nagasawa, R. Ikeda, Y.
1
0 mmol) was added and the reaction was monitored by
transferring aliquots (30 L) of the reaction mixture into a NMR
Nakaike and T. Konakahara, Tetrahedron Lett. 2011, 52
,
1
tube containing CDCl3 (0.6 mL) and subsequent
H NMR
3133; c) G. A. Olah, T. Yamato, P. S. Iyer and G. K. S. Prakash,
J. Org. Chem. 1986, 51, 2826. For a related concept in
reductive chemistry, see: d) S. Park, D. Bezier and M.
Brookhart, J. Am. Chem. Soc. 2012, 134, 11404.
spectroscopic analysis. Purification of the reaction mixture by
column chromatography (SiO ; cyclohexane/Et O 4:1) gave di(-
2
2
methyl-4-fluorobenzyl)ether (0.59 g, 91%).
1
0 a) T. S. Korstanje, J. T. B. H. Jastrzebski and R. J. M. Klein
Gebbink, ChemSusChem 2010, 3, 695; b) T. S. Korstanje, E. F.
General procedure for the etherification of alcohols
In a typical procedure, 4-fluoro-methylbenzylalcohol (60 L, 0.5
mmol) was added to a solution of CD Cl (1 mL) containing complex
de Waard, J. T. B. H. Jastrzebski and R. J. M. Klein Gebbink,
ACS Catal. 2012, , 2173; c) T. S. Korstanje, J. T. B. H.
Jastrzebski and R. J. M. Klein Gebbink, Chem. Eur. J. 2013, 19
3224.
11 a) J. R. Dethlefsen and P. Fristrup, ChemSusChem 2015,
2
2
2
1
(4.0 mg, 5.0 mol) and stirred for 5 min. Then Ph SiH (190 L, 1.0
2 2
,
,
mmol) was added and the progress of the reaction was monitored
1
by transferring aliquots (30 L) of the reaction mixture into a NMR
1
8
tube containing CDCl3 (0.6 mL) and subsequent
spectroscopic analysis.
H NMR
7
67; b) D. Lupp, N. J. Christensen, J. R. Dethlefsen and P.
Fristrup, Chem. Eur. J. 2015, 21, 3435.
Procedure for the synthesis of unsymmetrical ethers
12 a) G. W. Huber, S. Iborra and A. Corma, Chem. Rev. 2006,
106, 4044; b) A. Corma, S. Iborra and A. Velty, Chem. Rev.
2007, 107, 2411; c) Z. Zhang, J. Song and B. Han, Chem. Rev.
2017, 117, 6834.
4
-Fluoro-acetophenone (600 L, 5.0 mmol) was added to a solution
of complex 1 (4.0 mg, 5 mol) in CH Cl (0.75 mL) and MeOH (0.25
2
2
mL, 3:1 v/v solvent mixture) and stirred for 5 min. Phenylsilane
either 1.90 mL, 1.0 mmol at once; or 3.8 mL, 2.0 mmol in 10
(
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Journal Name
1
3 For selected examples, see: a) K. J. Miller and M. M. Abu- 26 Likewise, tBuOH did not yield the correspondiVniegw eArtthicleerOnbliunet
Omar, Eur. J. Org. Chem. 2003, 1294; b) H. K. Kalviri, C. F.
Petten and F. M. Kerton, Chem. Commun. 2009, , 5171; c)
only isobutene. The volatility of this product did not allow for
DOI: 10.1039/C7CY01832K
unambiguous quantification of reaction yields.
0
Y.-J. Zhang, W. Dayoub, G.-R. Chen and M. Lemaire, 27 Despite several attempts, isolation of this hydride species for
Tetrahedron 2012, 68, 7400; d) J. Wimberg, S. Meyer, S.
Dechert and F. Meyer, Organometallics 2012, 31, 5025. For
an example of a heterogeneous version, see: e) T. T. Pham, S.
P. Crossley, T. Sooknoi, L. L. Lobban, D. E. Resasco and R. G.
Mallinson, Appl. Catal. A, 2010, 379, 135.
further characterization failed. A related ruthenium(II)
hydride with a triazolylidene spectator ligand was recently
characterized, see: B. Bagh, A. McKinty, A. J. Lough and D.
W. Stephan, Dalton Trans. 2014, 43, 12842.
28 a) D. W. Stephan and G. Erker, Angew. Chem. Int. Ed. 2010,
1
1
4 A. Prades, R. Corberan, M. Poyatos and E. Peris, Chem. Eur. J.
49, 46; b) D. W. Stephan and G. Erker, Chem. Sci. 2014, 5,
2625.
2
008, 14, 11474.
5 For leading general references on N-heterocyclic carbene 29 This reactivity may be relevant for the conversion of alcohols
complexes, see: a) S. P. Nolan (Ed.), N-heterocyclic carbenes,
Wiley-VCH, Weinheim, Germany, 2014; b) D. Bourissou, O.
to an oxidized form to form an identical intermediate as
reached with the direct conversion of ketones and
aldehydes. A slow oxidation rationalizes the much lower
rates observed for ether formation when compared to the
conversion of carbonyl substrates. According to this model,
alcohol conversion is relying on the availability of a basic
nitrogen site, but ketone conversion is not. Basicity of the
triazolylidene N2 site has been proposed previously, see: a)
B. K. Keitz, J. Bouffard, G. Bertrand and R. H. Grubbs, J. Am.
Chem. Soc. 2011, 133, 8498; b) Y. Tulchinsky, M. A. Iron, M.
Guerret, F. P. Gabbai and G. Bertrand, Chem. Rev. 2000, 100
,
3
9; c) P. L. Arnold and S. Pearson, Coord. Chem. Rev. 2007,
51, 596; d) F. E. Hahn and M. C. Jahnke, Angew. Chem. Int.
2
Ed. 2008, 47, 3122; e) A. J. Arduengo and G. Bertrand, Chem.
Rev. 2009, 109, 3209; f) M. Poyatos, J. A. Mata and E. Peris,
Chem. Rev. 2009, 109, 3677; g) M. Melaimi, M. Soleilhavoup
and G. Bertrand, Angew. Chem. Int. Ed. 2010, 49, 8810; h) L.
Benhamou, E. Chardon, G. Lavigne, S. Bellemin-Laponnaz and
V. Cesar, Chem. Rev. 2011, 111, 2705.
Botoshansky and M. Gandelman, Nature Chem. 2011, 3, 525.
1
1
6 B. Marciniec, (Ed.), Hydrosilylation, a Comprehensive Review 30 Ketone reduction under 1 atm H was only observed at 80 °C,
2
on Recent Advances, Springer, 2009.
7 a) A. Petronilho, J. A. Woods, H. Mueller-Bunz, S. Bernhard 31 J. M. S. Cardoso, R. Lopes and B. Royo, J. Organomet. Chem.
and M. Albrecht, Chem. Eur. J. 2014, 20, 15775; for a related 2015, 775, 173.
not at RT.
system based on rhodium(I), see: T. V. Q. Nguyen, W.-J. Yoo 32 a) G. P. Mitchell and T. D. Tilley, Angew. Chem. Int. Ed. 1998,
and S. Kobayashi, Adv. Synth. Catal. 2016, 358, 452.
8 See Supporting Information for detailed characterization. Of
note, MS was inconclusive, see also: E. O. Nwoye and G. B.
Dudley, Chem. Commun. 2007, 0, 1436.
37, 2524; b) H. J. Liu, C. Raynaud, O. Eisenstein and T. D.
Tilley, J. Am. Chem. Soc. 2014, 136, 11473.
1
1
2
9 T. P. Brewster, A. J. M. Miller, D. M. Heinekey and K. I.
Goldberg, J. Am. Chem. Soc. 2013, 135, 16022.
0 J. A. Woods, R. Lalrempuia, A. Petronilho, N. D. McDaniel, H.
Müller-Bunz, M. Albrecht and S. Bernhard, Energy Environ.
Sci. 2014,
1 a) K. Riener, M. P. Höger, P. Gigler, F. E. Kühn, ACS Catal.
012, , 613; b) P. Gigler, B. Bechlars, W. A. Herrmann, F. E.
Kühn, J. Am. Chem. Soc. 2011, 133, 1589.
2 The reactivity of complex also provides a novel access to
7, 2316.
2
2
2
2
1
the formation of polyether compounds under mild
conditions. Thus, exposing 1,4-diacetylbenzene to a mixture
of complex
1 and Ph SiH yielded a polymeric mixture within
2 2
a few minutes. Not all starting material was converted,
presumably because of mass transfer limitations at high
polymer concentrations. Nonetheless, this reactivity may
constitute a complementary method to current methods
applied for the formation of polyethers, see e.g.: a) D. E.
Cane, W. D. Celmer and J. W. Westley, J. Am. Chem. Soc.
1
983, 105, 3594; b) M. Sakuth, T. Mensing, J. Schuler, W.
Heitmann, G. Strehlke and D. Mayer, Ethers, Aliphatic in
Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH,
Weinheim (Germany) 2010.
2
2
3 The quenching with pentane also provides an efficient
procedure to recover the catalyst precursor for repetitive
use.
4 Generation of hydrogen from alcohols and silanes along with
the corresponding alkoxosilane is well established, see for
examples: a) W. Sattler and G. Parkin, J. Am. Chem. Soc.
2
012, 134, 17462; b) X.-L. Luo and R. H. Crabtree, J. Am.
Chem. Soc. 1989, 111, 2527. However we have not observed
alcohol incorporation to form the corresponding
alkoxysilanes when using p-F-benzylalcohol as substrate and
hydrogen generation is most likely derived from the side
reaction of the silane with the iridium catalyst previously
reported.
2
5 A. Krüger and M. Albrecht, Chem. Eur. J. 2012, 18, 652.
8
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View Article Online
DOI: 10.1039/C7CY01832K
For ToC use only
A
promiscuous triazolylidene iridium complex efficiently
catalyses the etherification of ketones and aldehydes and also
promotes deoxygenation and hydrosilylation.
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