SNS-Ligands for Ru-Catalyzed Homogeneous Hydrogenation and Dehydrogenation Reactions

Article abstract of DOI:10.1021/acs.oprd.8b00142

A detailed study of literature-known and novel S-containing pincer-type ligands for ruthenium-catalyzed homogeneous hydrogenation and dehydrogenation reactions was carried out. The scope and limitations of these catalysts were carefully investigated, and it was shown that simple bench-stable SNS-Ru complexes can be used to facilitate the hydrogenation of a variety of different substrates at a maximum H₂ pressure of 20 bar under operationally simple, easy to scale up, glovebox-free conditions by using starting materials and reagents that do not require any special purification prior to use. It was also shown that such complexes can be used to catalyze the dehydrogenative coupling of alcohols and amines to get amides as well as for the dehydrogenative dimerization of alcohols to esters.

Full text of DOI:10.1021/acs.oprd.8b00142

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Full Paper
SNS-Ligands for Ru-Catalyzed Homogeneous
Hydrogenation and Dehydrogenation Reactions
Johannes Schörgenhumer, Axel Zimmermann, and Mario Waser
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00142 • Publication Date (Web): 08 Jun 2018
Downloaded from http://pubs.acs.org on June 8, 2018
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SNSꢀLigands for RuꢀCatalyzed Homogeneous
Hydrogenation and Dehydrogenation Reactions
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Johannes Schörgenhumer,a Axel Zimmermann,b* and Mario Wasera*
a)
b)
Institute of Organic Chemistry, Johannes Kepler University Linz, Altenbergerstr. 69,
4040 Linz, Austria
mario.waser@jku.at; Tel: +4373224685411; Fax: +437322468545402.
Patheon Austria, part of Thermo Fisher Scientific, St. Peterstr. 25, 4020 Linz, Austria
axel.zimmermann@patheon.com
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Graphical Abstract
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KEYWORDS: Homogeneous Catalysis; Pincer Type Ligands; Hydrogenation; Acceptorless
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Dehydrogenation; Carboxylic Acid Derivatives.
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ABSTRACT: A detailed study of literature known and novel Sꢀcontaining pincer type ligands
for Rutheniumꢀcatalyzed homogeneous hydrogenation and dehydrogenation reactions was
carried out. The scope and limitations of these catalysts were carefully investigated and it was
shown that simple bench stable SNSꢀRu complexes can be used to facilitate the hydrogenation of
a variety of different substrates at a maximum H2 pressure of 20 bar under operationally simple
and easy to scaleꢀup gloveboxꢀfree conditions by using starting materials and reagents that do not
require any special purification prior to use. It was also shown that such complexes can be used
to catalyze the dehydrogenative coupling of alcohols and amines to get amides as well as for the
dehydrogenative dimerization of alcohols to esters.
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Introduction
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The homogeneous hydrogenation of carboxylic acid derivatives, i.e. esters, is a transformation of
uttermost importance.1 Accordingly, the development of catalyst systems to carry out these
reactions under mild and environmentally benign conditions is at the forefront of catalysis
research, and a variety of different approaches relying on different metals and ligands have been
introduced over the last decade.1ꢀ8 Tridentate pincerꢀtype ligands have emerged as one of the
most important general structural platforms for homogenous transition metal catalysis.2
Pioneering work by Milstein3 and others,4 who introduced highly active Ruꢀbased PNN or PNP
pincer systems inspired the development of a variety of Ruꢀbased catalysts and lead to several
impressive applications for homogenous hydrogenation reactions of carboxylic acid derivatives.5
In addition, the last years have witnessed an increasing interest in the replacement of noble
metals by cheaper more abundant base transition metals like e.g. Mn or Fe. These catalyst
systems can also be used for robust hydrogenations of esters and other functional groups, albeit
they usually require higher catalyst loadings than the noble metalꢀbased systems.6 With respect
to potential larger scale industrial (ester) hydrogenations the use of highly active homogeneous
Ru catalysts represents an attractive opportunity. Hereby some of the main requirements are:
Low catalyst loadings; cheap ligands; operationally simple, scalable, and robust conditions
avoiding gloveꢀbox procedures; H2ꢀpressures below 20 bar that allow for hydrogenations in
standard multipurpose batch vessels. One catalyst system that fulfils a lot of these requirements
and which has proven its potential on multiton scale is Takasago’s RuꢀMACHO complex I,
which can even be used for the atmospheric pressure hydrogenation of esters when an additional
Nꢀheterocyclic carbene ligand is used (albeit requiring higher loadings).7
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Scheme 1. Targeted investigations of RuꢀSNS systems for hydrogenations and
dehydrogenations.
A different class of Ruꢀcomplexes that has shown very promising catalytic potential in the initial
investigations is Gusev’s SNSꢀbased catalyst IIa.8 This catalyst has shown very good activity for
ester hydrogenations at 50 bar and we were surprised to see that this complex has not been more
frequently used since that impressive first report. A literature research revealed that in general
SNS or SNN pincerꢀtype ligands have so far not received that much attention, which came as a
surprise to us, considering the simple synthesis of some of these ligands.8,9.10 We therefore
became interested in testing this platform for its potential to meet the above mentioned criteria
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(i.e. lower hydrogenation pressure and robust and operationally simple “gloveꢀbox free”
conditions that may allow for an industrial use) and carried out a broad and systematic testing of
different catalyst derivatives and conditions for homogeneous hydrogenations (i.e. of esters,
Scheme 1). In addition, Gusev’s and Yang’s groups also carried out detailed mechanistic studies
for this catalyst8,11 and Gusev also described the potential of their catalyst for the oxidative
dimerization of EtOH to EtOAc.8,11a,b Surprisingly, to the best of our knowledge this is the only
thoroughly investigated example for an acceptorless dehydrogenation reaction with SNSꢀ
containing pincerꢀtype ligands so far.12 We therefore also carried out a series of different
dehydrogenation experiments within this study (Scheme 1, lower reactions). Altogether, we now
wish to provide a detailed overview of the potential, robustness, and limitations of different
sulfurꢀbased pincerꢀtype ligandꢀcontaining Ruthenium complexes for different homogeneous
hydrogenation and dehydrogenation reactions that may also hold promise for eventually larger
scale applications.
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Results and Discussion
Ligands synthesized and tested:
We started our investigations by preparing13 a variety of easily accessible SNS complexes II in
analogy to Gusev’s work (Scheme 2).8
In addition to these simple aliphatic ligand systems we also decided to investigate pyridineꢀbased
SNS complexes III14 as well as the analogous SCS complexes IV.15 Besides these symmetric
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systems, we also synthesized a variety of dissymmetric Sꢀcontaining pincer ligands to access the
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pyridineꢀbased complexes VꢀVIII within this study.16
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Scheme 2. Ruꢀcomplex with Sꢀcontaining pincerꢀtype ligands tested in this study.
Homogeneous Hydrogenation:
To elucidate the catalytic potential of the Sꢀcontaining catalyst systems shown in Scheme 2 for
homogenous hydrogenation reactions under a maximum H2 pressure of 20 bar, we first tested
them for the hydrogenation of methyl benzoate 1a under a variety of different conditions (Table
1). In all these reactions we used dry degassed toluene as the solvent (unless otherwise stated)
and the catalysts and reagents were weighed, handled, and charged avoiding any glovebox
conditions. First experiments were carried out using the parent Gusev system IIa at 10 bar
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(entries 1ꢀ9). When using 0.1 mol% of the catalyst we observed almost 40% conversion after 5 h
at 60 °C and the reaction rate could significantly be improved by raising the reaction temperature
to 100 °C (entries 1ꢀ3). Unfortunately, when lowering the catalyst loading stepwise to 0.02 mol%
under otherwise identical conditions we observed a dramatic decrease in the reaction rates
(entries 4 and 5). Reactions carried out at different concentrations then revealed a pronounced
sensitivity of this system. While neat reactions performed well (entry 6), we were not able to
identify reproducible and robust conditions under higher dilutions (0.1M). Hereby the
conversions varied between almost zero up to 80ꢀ90% from experiment to experiment under
identical conditions (0.1M concentration of 1a, 10 bar H2, 0.1 mol% IIa, 10 mol% tꢀBuOK, 80ꢀ
100 °C). We carried out a broad variety of experiments (different qualities of solvents, base, …)
to understand the reasons for these seemingly random outcomes, but in the end we were only
able to achieve good and reliable conversions under these conditions when using a larger amount
of base and longer reaction times (entry 7).
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Table 1. Catalyst screening and identification of robust conditions for the hydrogenation of
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methylbenzoate 1a
Entrya Cat. (mol%)
Base (mol%)
T [°C]
H2 [bar]
t [h]
Conv. [%]b)
)
1
IIa (0.1%)
IIa (0.1%)
IIa (0.1%)
IIa (0.05%)
IIa (0.02%)
IIa (0.1%)
IIa (0.5%)
IIa (0.1%)
IIa (0.1%)
tꢀBuOK (10%) 60
tꢀBuOK (10%) 80
tꢀBuOK (10%) 100
tꢀBuOK (10%) 100
tꢀBuOK (10%) 100
tꢀBuOK (10%) 100
tꢀBuOK (50%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
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78
97
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6c)
7d)
8e)
9f)
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18h)
19i)
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IIa (0.1%)
IIa (0.05%)
IIa (0.1%)
IIa (0.1%)
IIa (0.1%)
IIa (0.1%)
IIa (0.1%)
IIb (0.1%)
IIb (0.1%)
IIb (0.1%)
IIc (0.1%)
IId (0.1%)
IIIa (0.1%)
IIIb (0.1%)
IIIc (0.1%)
IIId (0.1%)
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
NaOMe (10%) 80
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1
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97
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75
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NaH (10%)
KOH (10%)
80
80
88
63
Cs2CO3 (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 100
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
78
100 (96)g)
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3
<1
<1
<1
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IVa (0.1%)
IVb (0.1%)
V (0.1%)
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
tꢀBuOK (10%) 80
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5
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5
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<1
<1
<1
<1
<1
<1
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91
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VI (0.1%)
VIIa (0.1%)
VIIb (0.1%)
VIII (0.1%)
I (0.1%)
a) All screening reactions were carried out on 0.5ꢀ1 mmol scale in glass vials with magnetic
stirring (1200 rpm) using dry toluene (1M with respect to the ester) unless otherwise stated; b)
judged by 1H NMR; c) neat reaction; d) 0.1M in toluene; e) addition of 1 mol% silver 1,3ꢀ
dimethylimidazolꢀ2ꢀylidene (in analogy to Ref. 7b); f) addition of 2 mol% NaBH4; g) isolated
yield after filtration over a short plug of silica on 12 mmol scale; h) using dry THF as the solvent;
i) solventꢀfree.
Having shown that in general the hydrogenation of 1a at 10 bar is possible with reasonable
conversion when working at temperatures between 80ꢀ100°C, we next tested the potential of
additives to improve the performance and also to make the whole procedure more robust (i.e.
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with respect to the above mentioned concentration sensitivities). It was recently shown for Ruꢀ
MACHOꢀcatalyzed ester hydrogenations that the addition of carbene additives results in a highly
active system that even operates under an atmospheric H2 pressure (albeit requiring higher
catalyst and base loadings compared to high pressure autoclave conditions).7b Unfortunately, by
investigating the applicability and the potential of this strategy for SNS systems we observed a
clearly reduced catalytic performance (entry 8) and the same detrimental effect was observed
when adding NaBH4 (entry 9) (this effect was also present when working at higher pressures).
Unfortunately, we do not have a convincing (experimentꢀ and/or analysisꢀbased) explanation
why addition of these additives has such a negative effect on the reaction with RuꢀSNSꢀbased
complexes compared to the RuꢀMACHO system, as we could not isolated or analyze the
complex originating from the addition of the NHC to the catalyst (which would give an insight
if, for example one of the labile Sꢀligands is cleaved off, or if the new complex is sterically too
crowded to allow for a facile substrate coordination).
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Nevertheless, our experiments under 10 bar H2 pressure have unambiguously proven that the
standard Gusev catalyst systems IIa is a potentially effective ester hydrogenation catalyst under
gloveboxꢀfree conditions. However, it should be clearly pointed out that sometimes only minor
changes of the reaction parameters can significantly reduce the conversion rates and may lead to
less robust and less reproducible outcomes (i.e. under higher dilution). To establish a slightly
more robust procedure, we next carried out further investigations under a higher H2 pressure (20
bar, entries 10ꢀ16). It was clearly shown that under these conditions the hydrogenation proceeds
with a faster rate and we could reach almost complete conversion at 80 °C after 5 h (entry 10).
Again, lowering of the catalyst loading reduced the rate measurably (entry 11). Interestingly, it
seems that the reaction slows down with increasing conversion/time, as we noted a rather fast
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product formation after 1 h already (75% conversion, entry 12), but it takes another 4 h to reach
almost complete product formation. When testing different bases, we found that others allow for
reasonable reaction rates too (entries 13ꢀ16), but not as high as with tꢀBuOK. With high yielding
conditions established (entry 10), we then put our focus on the screening of the different catalysts
shown in Scheme 2. We first tested the Gusevꢀtype systems II and found that the dimethylꢀ
containing complex IIb is even slightly more reactive than the diethylꢀbased IIa (entry 17, this
experiment was reproduced several times and also carried out on 12 mmol scale without any
difference in performance giving 2a in an isolated yield of 96% after filtration over a short plug
of silica and removal of the solvent and MeOH). We also tested this catalyst in THF (entry 18)
and under solventꢀfree conditions (entry 19) but in both cases the conversion was measurably
slower compared to toluene as the solvent. On the other hand, increasing the steric bulk on the
sulfide (complexes IIc and IId) clearly lowered the catalytic activity (entries 20 and 21). By
considering the wellꢀaccepted mechanism for such hydrogenation reactions8, this experimental
observation may be rationalized by the strong increase of steric bulk around the Ruꢀcenter, which
as a consequence will hinder substrate coordination (thus slowing down the overall reaction).
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Inspired by the potential and the rich history of pyridineꢀcontaining PNP and PNN Ruꢀ
complexes (i.e. Milstein’s system3), we also synthesized and tested the pyridineꢀbased SNS
complexes III.14 Very surprisingly, none of these systems showed any noteworthy catalytic
potential for the hydrogenation of ester 1a at 20 bar (entries 22ꢀ25). These complexes also did
not perform better under more forcing conditions (higher T and pressure) or when using higher
catalyst loadings. These results, which are in very sharp contrast to the Milstein system, may to
some extent by explained by the relatively high acidity of the benzylic protons of these
complexes, which under the basic reaction conditions can lead to ylideꢀtype structures and also
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the formation of dinuclear catalytically lessꢀreactive complexes as reported by Milstein’s group
for pyridineꢀbased SNP Ruꢀcomplexes.12 Thus, it also comes as no big surprise that the
structurally related pyridineꢀbased systems V, VI, and VII do not show any catalytic potential
for this ester hydrogenation (entries 28ꢀ31). Benzeneꢀbased NCN pincer type ligands have
recently attracted some interest for homogenous Ruꢀcatalyzed hydrogenation reactions.17
Analogous Ni and Pdꢀbased SCS complexes have been reported before15 and for our screening
we also tested the SCS Ruꢀcomplexes IV (entries 26 and 27), which however did not allow for
any alcohol formation under these hydrogenation conditions (higher catalyst loadings or pressure
were not successful either), which is not a big surprise when considering the previous
observations with catalysts III, V, VI, and VII. All these results clearly illustrate that aliphatic
amine linkers and sterically less crowded sulfide groups are necessary for SNSꢀbased
hydrogenation catalysts. Therefore, we finally tested the pyridineꢀbased NNS complex VIII and,
as expected, this was the only other system (apart from complexes II) that could successfully be
employed for the reduction of 1a (entry 32). Very interestingly, during our early investigations
with this catalyst de Vries and coꢀworkers independently reported this system to be an efficient
hydrogenation catalyst for aromatic esters and α,βꢀunsaturated esters at 30 bar H2 pressure.16
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Summing this broad screening of different Sꢀcontaining pincer ligands for Ruꢀcatalyzed ester
hydrogenations up, it was clearly shown that the Gusevꢀtype catalysts II clearly outperform all
the other systems tested herein. Especially the sterically less crowded derivatives IIa and IIb
show very high reactivities, which are at least in the same range as the RuꢀMACHO system (see
entry 33 for a control experiment), and allow for fast hydrogenation reactions at a maximum of
20 bar H2 pressure. It is fair to say that we did most of the screening with a relatively high
catalyst loading of 0.1 mol% but our results also show that lower catalyst loadings are in general
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possible at this pressure but lead to reduced reaction rates. One potential option to achieve faster
hydrogenations would be the use of a larger excess of base or (as was clearly shown by Gusev’s
group in their seminal contribution)8 to increase the H2 pressure. The handling of these systems
does not require any special precautions and all reactions were carried out without using a
glovebox or any special Schlenk techniques with commercially available starting
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materials/reagents that were not purified any further prior to use. The one parameter that needs to
be controlled is the quality of the used toluene, which needs to be dried and degassed with
standard laboratory techniques (but again no glovebox or Schlenk techniques are required).
Altogether, we thus believe that the Gusev system II is a promising platform for relatively lowꢀ
pressure hydrogenation reactions under operationally simple conditions, but a certain sensitivity
towards a change in the conditions can be observed. The application scope of catalyst IIb for the
hydrogenation of a variety of different esters 1, aldehydes and ketones 5 and the other substrates
6ꢀ9 was investigated next. For comparison of the reactivity of these substrates and the
performance of this catalyst system all reactions were carried out on 1 mmol substrate scale
under exactly the same 20 bar conditions depicted in Table 1, entry 17. Different aryl esters 1aꢀ
1f reacted readily, although it was clearly shown that electronꢀwithdrawing (e.g. CF3) as well as
electronꢀdonating (MeO or NH2) groups lower the conversion rate. In all these cases higher
catalyst loadings, longer reaction times or higher pressure (as demonstrated by Gusev8) will
allow for complete conversions. Surprisingly, the orthoꢀsubstituted esters 1g and 1h tested in this
study turned out to be more or less unreactive (also with higher catalyst loadings) under these
reducedꢀpressure conditions, which is in sharp contrast to electronically similar paraꢀsubstituted
esters (compare 1d and 1h). On the other hand, the simple aliphatic esters 1iꢀ1l were all
hydrogenated readily.
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Scheme 3. Application scope for the hydrogenation of different substrates under 20 bar H2
pressure using the SNS Ru complex IIb (Isolated yields after filtration over a short plug of silica
gel were > 95% in those cases were complete conversion was achieved).
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An interesting result was obtained with the α,βꢀunsaturated ester 1m. De Vries and coꢀworkers
have recently shown that the hydrogenation of such substrates with the NNS catalyst VIII can
give the corresponding allylic alcohols with high selectivities.16 In sharp contrast, the catalyst IIb
was found to hydrogenate the C=C and C=O bond of substrate 1m equally under the chosen
conditions. We next tested a few simple aromatic aldehydes (5aꢀ5e) and found that apart from
the NO2ꢀbased aldehyde 5b all of them reacted rather fast, even the orthoꢀsubstituted 5e (please
compare with the result obtained for the analogous ester 1h). We tried to address the
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hydrogenation of substrate 5b under different conditions but we were not able to achieve a
reasonable conversion under more forcing conditions. To test whether the NO2ꢀgroup somehow
deactivates the catalyst, we performed the hydrogenation of methylbenzoate (1a) in the presence
of 10 mol% nitrobenzene (9) and found that the ester hydrogenation rate is significantly reduced
hereby (43% after 5 h). Interestingly however, the NO2ꢀgroup itself is not reduced under these
conditions (which was also shown in an experiment using just compound 9). Another result that
we found somewhat surprising was the relatively low conversion rate of cyclohexane
carbaldehyde (5f) under these conditions. On the other hand, simple ketones 5gꢀ5i as well as the
aromatic imines 6a and 6b reacted smoothly and in the case of the α,βꢀunsaturated butanone 5h
complete hydrogenation of the C=C double bond and the carbonyl group was observed within 5
h reaction time. We also tested the potential of this hydrogenation system for the reduction of
azides and observed more or less full conversion of diazide 7 to the corresponding diamine under
the standard conditions. Finally, hydrogenation of styrene 8a and cyclohexene 8b was possible
as well, but with a reduced reaction rate compared to most of the other substrates tested herein.
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Summing this broad screening of different substrates up, we found that the Gusevꢀtype system
IIb is a useful catalyst to carry out homogenous hydrogenation reactions of esters, aldehydes,
ketones, imines, azides and olefins under a maximum H2 pressure of 20 bar under operationally
simple and glove boxꢀfree conditions without any further purification of the used commercial
starting materials and reagents. In most of those cases where the conversion was somewhat
slower, longer reaction times and/or higher catalyst loadings and H2 pressure allow for better
conversions (please compare also with the results obtained by Gusev at 50 bar H2 pressure8).
Some observed limitations under these conditions were the low reactivity of orthoꢀsubstituted
esters as well as the deactivating effect of NO2ꢀgroups on the catalyst performance.
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Acceptorless Dehydrogenation:
It has been wellꢀdocumented in the past that a lot of the recently introduced pincerꢀtype
hydrogenation catalysts also allow for the reverse acceptorless dehydrogenation reactions.18,19
This potential can either be exploited for borrowing hydrogen catalysis,19 or for oxidative
coupling reactions like the formation of esters from two alcohols or the formation of amides by
coupling of an alcohol with an amine.18 Gusev’s group has shown that their SNS Ruꢀsystem can
facilitate the oxidative dimerization of EtOH to access EtOAc8 and also carried out detailed
mechanistic studies for this transformation with different catalyst systems.11 Surprisingly
however, apart from this report and a study by Milstein et al. on RuꢀPNS systems12 the potential
of Sꢀcontaining pincer type systems for such acceptorless dehydrogenation reactions has so far
only rather sparingly been investigated. We thus tested the different Sꢀcontaining Ru complexes
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shown in Scheme 2 for both, the oxidative ester and amide syntheses under a variety of different
conditions.
7
8
9
Table 2. Catalyst screening and identification of suited conditions for the formation of amide 4a.
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Entrya)
Cat. (mol%)
IIb (0.1%)
IIb (0.1%)
IIb (0.1%)
IIb (0.1%)
IIb (0.1%)
IIb (0.1%)
IIb (0.1%)
IIb (0.1%)
IIb (0.05%)
Base (mol%)
2a : 3a
1 : 1
Conc.b)
2M
Conv. [%]c)
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2
3
4
5
6
7
8
9
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (7%)
tꢀBuOK (15%)
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
30
13
56
43
56
54
56
11
<1
1.5 : 1
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
2M
2M
2M
2M
1M
2.7M
4M
2.7M
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IIb (0.5%)
IIb (0.1 + 0.1%)d)
IIb (0.1%)
IIb (0.1%)
IIb (0.1%)
IIb (0.1%)
IIa (0.1%)
IIc (0.1%)
IId (0.1%)
IIIa (0.1%)
IVa (0.1%)
V (0.1%)
tꢀBuOK (10%)
tꢀBuOK (10%)
NaH (10%)
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
2.7M
2.7M
2.7M
2.7M
2.7M
2.7M
2.7M
2.7M
2.7M
2.7M
2.7M
2.7M
2.7M
2.7M
2.7M
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NaH (20%)
NaOMe (10%)
K2CO3 (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
tꢀBuOK (10%)
<1
17e)
2
2
<1
<1
<1
2
VIIb (0.1%)
VIII (0.1%)
I (0.1%)
<1
16
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a) All reactions were run for 24 h at 110 °C on 2 mmol scale in dry toluene using glass vials with
magnetic stirring (600 rpm); b) based on the limiting reagent; c) judged by 1H NMR; d) 0.1 mol%
catalyst in the beginning and after 24 h another 0.1 mol% of catalyst were added and stirred for
further 24 h; e) around 20ꢀ25% of benzylbenzoate were formed.
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Considering the lack of previous reports concerning the potential of Sꢀbased complexes IIꢀVIII
for the synthesis of amides 4 by reacting simple alcohols 2 with amines 3, we first carried out a
detailed screening of different conditions and catalysts for the parent reaction between
benzylalcohol 2a and benzylamine 3a (Table 2). We started the screening by using 0.1 mol% of
the complex IIb in combination with 10 mol% tꢀBuOK in dry toluene (110°C). First experiments
showed that it is beneficial to use a slight excess of the amine component (entries 1ꢀ3) to
suppress the competing dimerization of benzylalcohol 2a (giving the corresponding ester). When
using less base (entry 4), the yield dropped somewhat, while using more base did not increase the
conversion rate measurably (entry 5). Running the reaction under more diluted conditions had no
pronounced effect (entry 6), while higher concentrations were only tolerated up to 2.7M without
negatively affecting the conversion (entries 7 and 8). Varying the catalyst amount showed that
the reaction more or less totally stops at reduced loadings of 0.05 mol% already (entry 9). On the
other hand, higher catalyst amounts lead to a noticeable increase of the conversion (entry 10). At
this point we carried out a variety of experiments at different temperatures, longer reaction times,
testing other solvents, and also in the presence of air or oxygen and/or under a slight vacuum to
remove the evolving H2 (and thus suppress an eventual back reaction). Unfortunately, none of
these attempts lead to higher conversions. In all cases we observed stalling of the reaction after
reaching a certain conversion (50ꢀ60% when using 0.1 mol% catalyst) and longer reaction times
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had no positive effect anymore, which can only be rationalized by some catalyst deactivation
during the reaction. One option to slightly overcome this limitation is by adding additional fresh
catalyst after some time (entry 11), but also hereby no complete conversion could be reached. A
variety of other bases were tested, but none of them allowed for similar conversions as tꢀBuOK
(entries 12ꢀ15). With reasonable conditions for catalyst IIb found (entry 7), we next tested the
other Sꢀcontaining complexes IIꢀVIII (entries 16ꢀ23). Based on the lessons learnt during the
hydrogenation reaction (i.e. illustrating the need for small amine linkerꢀcontaining SNS ligands)
it came as no big surprise that most of the other systems did not allow for any noticeable amide
formation. A very surprising outcome however was observed with the parent Gusev system IIa,
which resulted in much slower amide formation than the very similar complex IIb (entry 16).
Interestingly, we hereby realized that catalyst IIa leads to a significant amount of benzylbenzoate
formation instead. This alcohol dimerization was very much suppressed in all the experiments
with IIb and these results show a very pronounced (but hard to understand) difference in the
catalytic behavior of these two seemingly similar complexes (see the discussion below for
further details on the ester formation).
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Having shown that complex IIb clearly outperforms the other catalysts tested herein for the
dehydrogenative amide formation between alcohols and amines we next investigated the
application scope for this transformation (Scheme 4). For comparison all reactions were carried
out under exactly the same conditions using 0.1 mol% of the catalyst (higher catalyst loadings
would allow for higher yields as shown in Table 2). Variation of the amine component 3 showed
that different aniline derivatives can be successfully employed to give the products 4bꢀ4e, albeit
a significantly slower reaction towards 4e (compared to the other derivatives) was observed.
Also, the pyridineꢀcontaining amide 4f was formed in approximately 50% after 24 h reaction
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time, whereas increasing the steric bulk on the amine partner was not tolerated (4g). Simple
primary aliphatic amines like nꢀbutylamine can be used too (product 4h), while the incorporation
of a secondary amine to access amide 4i failed. Variations of the alcohol partner 2 were tolerated
as well, as illustrated in the synthesis of the amides 4jꢀ4m, although hereby the coupling with
benzylic amines performed better than with aniline derivatives (compare the results for products
4j and 4k).
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Scheme 4. Application scope for the acceptorless amide formation using the SNS Ru complex
IIb.
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Finally, we also carried out a brief screening of the different catalysts for their potential to
catalyse the dehydrogenative alcohol to ester dimerization. As we observed some benzylalcohol
(2a) dimerization to benzylbenzoate (1n) in some of the amideꢀforming experiments, we used
this transformation as the model reaction for our investigations (see Table 3 for the most
illustrative results). The most striking observation from the initial testing of the different
catalysts for the dimerization of 2a in toluene was that the standard Gusev catalyst IIa clearly
outperforms all other derivatives (see entries 1ꢀ8). This higher alcohol dimerization potential of
IIa compared to the methylꢀderivative IIb was already observed in the amide formation
screening (see entry 16, Table 2) and we therefore further optimized the dimerization conditions
for catalyst IIa.
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Table 3. Catalyst screening and identification of suited conditions for the formation of ester 1n.
Entrya)
Cat. (mol%)
IIa (0.1%)
IIb (0.1%)
IIc (0.1%)
Base (mol%)
tꢀBuOK (1%)
tꢀBuOK (1%)
tꢀBuOK (1%)
Conv. [%]b)
1
2
3
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IIIa (0.1%)
IVa (0.1%)
tꢀBuOK (1%)
tꢀBuOK (1%)
1
5
<1
<1
<1
27
43
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50
82
91
7
8
9
6
VIIb (0.1%)
VIII (0.1%)
I (0.1%)
tꢀBuOK (1%)
tꢀBuOK (1%)
tꢀBuOK (1%)
tꢀBuOK (2%)
tꢀBuOK (10%)
NaH (1%)
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9
IIa (0.1%)
IIa (0.1%)
IIa (0.1%)
IIa (0.1%)
IIa (0.1%)
IIa (0.2%)
IIa (0.5%)
10
11
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14
15
NaOMe (1%)
Cs2CO3 (1%)
tꢀBuOK (1%)
tꢀBuOK (1%)
a) All reactions were run for 24 h at 110 °C on 6 mmol scale in dry toluene (3M) using glass vials
with magnetic stirring (600 rpm); b) judged by 1H NMR.
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In contrast to the alcoholꢀamine coupling, an excess of base was found to have a negative effect
on the esterꢀformation (entries 9 and 10). Different bases (entries 11ꢀ13) can be used and
especially other alkoxides like NaOMe allow for similarly good conversion as tꢀBuOK. We also
tested different solvents, dilutions and temperatures, as well as working under a slightly reduced
pressure (to remove the evolving H2), but none of these changes allowed for a higher conversion.
It was observed again that the reaction proceeds with a relatively fast initial rate and then slows
down significantly over time. Therefore, the only way to improve the conversion further was by
using larger catalyst loadings (entries 14 and 15).
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We then briefly tested a few simple alcohols under the developed conditions in toluene and
found that the outcome of this reaction is rather sensitive to the nature of the employed alcohol 2
(Scheme 5). While propanol reacted reasonably fast, we found that ethanol gave only 28% of
EtOAc under these conditions. This result is in sharp contrast to Gusev’s report who found that
the corresponding neat reaction with NaOEt as the base allows for up to 97% conversion.8 These
observations clearly show that this alcohol dimerization is obviously a rather sensitive process
which requires a careful fineꢀtuning of the reaction conditions for a given substrate. We also
tested the mixed esterꢀformation by reacting benzylalcohol 2a with methanol 2b but found that in
all cases, also when using different stoichiometric ratios, the benzylalcohol dimerization is
significantly faster than the formation of methyl benzoate.
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Scheme 5. Dehydrogenative ester formation using the SNS Ru complex IIa.
Conclusion
Summing our broad screening of different Sꢀcontaining pincer type ligands for Ruꢀcatalysed
homogeneous hydrogenation and dehydrogenation reactions up, it was clearly shown that the
rather simple aliphatic amine linkerꢀbased SNSꢀsystems developed by Gusev’s group are by far
the most promising amongst the tested complexes. The structurally lessꢀcrowded ethylꢀbased
system IIa and the methylꢀbased IIb show reasonable hydrogenation potential under
operationally simple and gloveboxꢀfree conditions and can be used at H2 pressures below 20 bar
for a broad variety of different substrates. In some cases, it was shown that the application of
these catalysts under these conditions may require some special fineꢀtuning of the conditions for
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given substrates. In addition, we found that under these lower pressure conditions the reactions
slow down measurably when lowering the catalyst loading or when carrying out the reactions at
higher dilutions. On the other hand, the hydrogenation rates can be improved by using higher
amounts of bases or working at higher temperatures/pressures. We have also shown that the
catalysts hold potential for acceptorless dehydrogenation reactions. Interestingly the ethylꢀbased
system IIa was betterꢀsuited for the oxidative alcohol dimerization to access esters, while the
methylꢀbased system IIb clearly outperformed all the other complexes for amide formations.
Altogether, we thus hope that we could show the potential as well as the limitations of these
easily accessible catalysts for homogeneous catalysis under operationally simple conditions,
which also qualify them for potential applications on larger scales.
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Experimental Section
General Information
1Hꢀ and 13CꢀNMR spectra were recorded on a Bruker Avance III 300 MHz spectrometer and
were referenced on the solvent peak. High resolution mass spectra were obtained using a Thermo
Fisher Scientific LTQ Orbitrap XL with an Ion Max API Source.
The reactions were performed under an Arꢀatmosphere unless stated otherwise.
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Organic Process Research & Development
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All the catalyst handling prior to applying hydrogen was done under air without using any glove
box or Schlenk techniques. Reagentꢀgrade toluene was distilled over Na prior to use. All other
chemicals were used in the commercially available qualities without any further purification or
synthesized and purified as described previously (compounds 1b, 1d, 1f, 1g, 1h, 6a, 6b).20 All
hydrogenation and dehydrogenation products are literature known compounds and the
experimental data fit those reported recently and all experimental details and analytical data can
be found in the online supporting information.
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Catalyst Syntheses:
Catalyst IIa was prepared as described recently.8 The analytical details for all the ligands and
catalysts that were not active can be found in the online supporting information.
Catalyst IIb:
Similar to known literature,8 sodium methanethiolate (0.63 g, 9 mmol) and solid NaOH (219 mg,
5.47 mmol) were taken up in MeOH (3 mL) and stirred for 10 min at room temperature. Then, a
solution of bis(chloroethyl)amine hydrochloride (0.75 g, 4.2 mmol) in MeOH (3 mL) was added
dropwise. The mixture was allowed to stir overnight at room temperature. The solvent was
evaporated and the resulting slurry was washed three times with nꢀpentane. The combined
pentane phases were then filtered through a plug of basic Al2O3. After evaporation of the solvent
and drying in vacuo, the ligand 11b was obtained as a colourless oil in 81% yield (562 mg).
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