Direct trans-Selective Ruthenium-Catalyzed Reduction of Alkynes in Two-Chamber Reactors and Continuous Flow

Article abstract of DOI:10.1021/acscatal.6b01045

An efficient trans-selective hydrogenation of alkynes under low hydrogen pressure and low reaction temperatures is reported, applying a commercially available ruthenium hydride complex. The developed reaction conditions, which tolerate a variety of functional groups, are carried out in a two-chamber setup with ex situ generated hydrogen. The reaction setup is highly suitable for deuterium labeling. The trans-selective hydrogenation was extrapolated to a transfer hydrogenation protocol, employing a packed bed immobilized ruthenium hydride catalyst in continuous flow with a retention time of only 10 min.

Full text of DOI:10.1021/acscatal.6b01045

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Article
Direct trans-Selective Ruthenium-Catalyzed Reduction of
Alkynes in Two-Chamber Reactors and Continuous Flow
Karoline T. Neumann, Sebastian Klimczyk, Mia N. Burhardt, Benny
Bang-Andersen, Troels Skrydstrup, and Anders T. Lindhardt
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01045 • Publication Date (Web): 07 Jun 2016
Downloaded from http://pubs.acs.org on June 8, 2016
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Direct TransꢀSelective RutheniumꢀCatalyzed Reduction of Alkynes in Twoꢀ
Chamber Reactors and Continuous Flow
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Karoline T. Neumann§, Sebastian Klimczyk¥, Mia N. Burhardt§, Benny BangꢀAndersen‡, Troels
Skrydstrup§ and Anders T. Lindhardt¥,*
§Carbon Dioxide Activation Center (CADIAC), Department of Chemistry and the Interdisciplinary
Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark
¥ Carbon Dioxide Activation Center (CADIAC), Interdisciplinary Nanoscience Center (iNANO),
Department of Engineering, Aarhus University, Finlandsgade 22, 8200 Aarhus N, Denmark.
‡Lundbeck Research Danmark H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
Abstract
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An efficient transꢀselective hydrogenation of alkynes under low hydrogen pressure and low reaction
temperatures is reported applying a commercially available rutheniumꢀhydride complex. The
developed reaction conditions, which tolerate a variety of functional groups, are carried out in a twoꢀ
chamber setꢀup with ex-situ generated hydrogen. The reaction setꢀup is highly suitable for deuterium
labeling. The trans-selective hydrogenation was extrapolated to a transfer hydrogenation protocol,
employing a packed bed immobilized ruthenium hydride catalyst in continuous flow with a retention
time of only 10 minutes.
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Keywords: hydrogenation, alkynes, rutheniumꢀcatalysis, deuteriumꢀlabeling, transꢀalkenes, continuous
flow
Introduction
Olefins are biologically important structures, present in a plethora of pharmaceuticals, natural products
and fragrances.1 The stereochemistry of the carbon–carbon double bond is decisive for the biological
activity, and hence the ability to construct these olefins in a stereoselective manner is highly desirable.
One approach relies on the partial metalꢀmediated hydrogenations of internal alkynes. The formation of
cisꢀolefins generally relies on the use of Lindlar’s catalyst, due to its high functional group tolerance
and selectivity against overꢀreduction.2 However, the selective conversion of internal alkynes to transꢀ
alkenes still remains a challenge. Dissolving metal reductions is one approach, but is limited due to
poor functional group tolerance.3 More recent processes rely on transition metalꢀcatalyzed semiꢀ
hydrogenations, but many of these apply organic or inorganic acids as hydrogen sources, which can
restrict the functional group tolerance, and in general require reaction temperatures ranging from 80–
145 °C.4 Other protocols rely on H2O as the hydrogen source in the presence of a reductant in
combination with elevated reaction temperatures.5 Twoꢀstep protocols to transꢀalkenes have also been
published, such as the Ruꢀcatalyzed selective transꢀhydrosilylation followed by protodesilylation.6
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In 2013, two reports on transition metal catalyzed transꢀselective hydrogenations of alkynes applying
hydrogen gas (H2ꢀgas) were published by the groups of Fürstner with [Cp*Ru(cod)Cl],7 and Milstein
employing an iron pincer complex.8 Remarkably, in the former case internal aliphatic alkynes show
high transꢀselectivity and a mechanism involving a metalꢀcarbene intermediate has recently been
suggested.7 Both methods are run at hydrogen pressures up to 10 bars.
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In this paper, we wish to report an operationally simple, mild and highly transꢀselective hydrogenation
of di(hetero)arylꢀ and alkyl–arylacetylenes, applying a simple and commercially available ruthenium–
hydride catalyst. A particularly attractive feature of this protocol is the possibility to run the semiꢀ
o
hydrogenations at reaction temperatures as low as 45 C, and applying a maximum of only 10
equivalents of H2ꢀgas. The reactions were conducted in a twoꢀchamber system COware,9 with
hydrogen being generated ex situ. Given the simple setup the method can easily be adapted to
deuterium labelling using ex situ generated D2ꢀgas.10 Next, successful immobilization of the ruthenium
catalyst onto triphenylphosphineꢀmodified styrene beads allowed the construction of a continuous flow
packed bed reactor. Using formic acid at the hydrogen donor this afforded a continuous flow protocol
with a retention time of only 10 minutes.
Results and Discussion
The optimization of the transꢀhydrogenation took its starting point in a catalyst screening using
diphenylacetylene (1) as the test substrate (Table 1). First, the catalyst employed by Fürstner and coꢀ
workers was reexamined using our twoꢀchamber system and 10 equiv. of hydrogen gas providing a
partial pressure of only 3 bars. This provided a 75% yield of the desired transꢀstilbene (2) along with
25% of the undesired fully reduced alkane (4, Table 1, entry 1) paralleling Fürstner’s earlier published
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results.7 A number of other Ruꢀcatalysts were then tested in order to achieve full selectivity. Several of
the tested complexes did not display any reactivity with only recovered starting material 1 (Table 1,
entries 3, 5, 6 and 10). For other complexes conversion was obtained, however, the selectivity was poor
(Table 1, entries 2 and 8). When either Ru(PPh3)3Cl2 or Ru(PPh3)4H2 was applied, full conversion was
attained but with selectivity towards the cisꢀstilbene (3, Table 1, entries 4 and 9). To our delight,
Ru(PPh3)3CO(Cl)H proved not only to be active for the semiꢀhydrogenation, but importantly, only
generated the desired transꢀstilbene 2 (Table 1, entry 7). It was furthermore possible to reach the same
result with a catalyst loading of only 2.5 mol% (Table 1, entry 11). Nevertheless, lowering the catalytic
loading to 1 mol%, resulted in a drop in conversion, while still retaining the high trans-selectivity
(Table 1, entry 12).11
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Table 1. Catalyst screening for the Ruꢀcatalyzed semiꢀhydrogenationa,b
1 [%]
0
2 [%]
3 [%]
0
4 [%]
Entry [Ru]
Cp*Ru(cod)Cl
75
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0
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Ru(Meꢀallyl)2cod
[(pꢀcymene)RuCl2]2
Ru(PPh3)3Cl2
Ru(acac)3
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[RuCp(CO)2]2
Ru(PPh3)3CO(Cl)H
Ru3(CO)12
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0
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96
0
Ru(PPh3)4H2
RuCl3
0
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100
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11c
12d
Ru(PPh3)3CO(Cl)H
Ru(PPh3)3CO(Cl)H
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aH2 was generated ex situ from Zn and HCl (6 M). See experimental section. bProduct distribution is determined
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by GC analysis. c2.5 mol% of Ru(PPh3)3CO(Cl)H was employed. d1 mol% of Ru(PPh3)3CO(Cl)H was used.
The reaction was also examined using a H2ꢀballoon (1 atm partial pressure of H2) resulting in only 50%
conversion, but still with transꢀselectivity (results not shown). Finally, a small solvent screening was
performed, showing that the reaction worked equally well in THF and toluene. However, running the
reaction in MeCN and MeOH impeded the catalytic activity as only low conversion was observed.12
Simple mechanistic experiments on diphenylacetylene indicate that the transꢀhydrogenation occurs in a
twoꢀstep process with the initial reduction to cisꢀstilbene. cisꢀStilbene is then isomerized into the
desired transꢀstilbene under the same catalytic conditions (see Supporting Information Figures S1 and
S2). It is interesting to note that hydrogen/deuterium exchange occurs quite effectively on transꢀ
stilbene under the developed conditions without formation of the fully reduced 1,2ꢀdiphenylethane
(Figure S2).
With an efficient catalytic system for the transꢀselective semiꢀhydrogenation of diphenylacetylene in
hand, we set out to examine the functional group tolerance and hence the generality of the developed
reaction conditions (Scheme 1). Aromatic alkynes bearing either electron withdrawingꢀ (5a, 5b, 5g, 5h)
or donating groups (5d, 5e, 5g) were successfully hydrogenated in excellent yields and selectivity.
Furthermore, a wide range of reducible functional groups, such as nitroꢀ (5j), cyanoꢀ (5l) or various
carbonylꢀfunctionalities (5m, 5k, 5p) were tolerated under the developed reaction conditions and
delivered the desired transꢀolefins in good to excellent yields. When the reaction was performed in the
presence of an aldehyde, the carbonyl group was reduced along with the alkyne in an 88% yield
(compound 5f). As depicted in Scheme 1, various heteroaromatic alkynes, bearing pyridine (5o),
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pyrazole (5q), (benzo)thiopheneꢀ (5u, 5v) or benzofurane (5w) moieties were readily reduced in yields
ranging from 61% to 89% using hydrogen gas. When alkynes bearing arenes with ortho-substituents
o
were examined, the reactivity turned out to be poor at 45 C. However, these compounds could be
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selectively hydrogenated by increasing the reaction temperature to 90 °C in toluene. Thus, methoxy
(5n, 5r), methyl (5r–5s) and isopropyl (5t) substituents were tolerated in the orthoꢀposition, affording
the desired products in yields ranging from 91‒99%. Remarkably, even the diarylꢀalkyne bearing three
methyl groups in the orthoꢀpositions was hydrogenated trans-selectively in an 88% yield (compound
5s). It was also possible to hydrogenate alkynes bearing a trimethylsilyl group (5y, 94%) or an aliphatic
group such as ethyl (5x, 89%). Finally, when diꢀaliphatic alkynes were examined, only complicated
mixtures of products with double bond migration was observed. Scaling the semihydrogenation of
diphenylacetylene up to a 10 mmol scale proved to be successful as well. This led to the isolation of the
transꢀstilbene in a 99% yield only requiring 0.001 mol% of the ruthenium catalyst and 1.2 equivalents
of hydrogen if the reaction was run at 90 oC.
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aAlkyne (0.2 mmol, 0.2 M). H2 was generated ex situ from Zn (3.4 mmol) and HCl (1 mL, 6 M). All yields refer
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to pure isolated material. bReaction performed on a 10 mmol scale using 0.001 mol% Ru(PPh3)3CO(Cl)H and 1.2
o
c
d
equiv. of H2 at 90 C. Starting from 4ꢀ(phenylethynyl)benzaldehyde. D2 was used and generated ex situ from
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e
Zn (3.4 mmol) and DCl (1 mL, 6 M). Full deuteration of the alkene and 70% deuteration of the methylene
group. fReaction was conducted at 60 °C in toluene. gReaction was conducted at 90 °C in toluene.
Scheme 1. Transꢀselective semiꢀhydrogenation of internal alkynesa
Next, we examined the propensity of terminal alkynes to be selectively reduced to the corresponding
styrenes. This would provide the opportunity to prepare deuterated styrenes applying D2 instead of H2.
Only a few examples exist on the synthesis of deuterated styrenes, either starting from the deuterated
alkyne, or by hydrogenꢀdeuterium exchange with the styrene.13 The reaction with terminal alkynes had
to be slightly optimized, as overꢀreduction was observed to a large degree when employing the standard
o
reaction conditions. Gratifyingly, it was found that the reduction could be carried out at 20 C for 18 h
giving the desired styrene in an 86% yield along with a 14 % yield of the fully reduced compound.
From time experiments, we observed that full conversion to the styrene could be achieved after 3 h
1
(selectivity >95%:5% styrene:fully reduced, as observed by H NMR analysis of the crude reaction
mixture). Other successful semireductions of terminal alkynes are depicted in Scheme 2. Good to
excellent yields were obtained in all cases (6aꢀ6f), and switching to deuterium gas led to high
deuterium incorporation as seen for 6eꢀd3. Interestingly, triꢀdeuteriation was observed for the olefinic
part of 6eꢀd3 presumably originating from nonꢀselective readdition of the active RuꢀD catalyst after the
primary reduction event. Rotation of the carbonꢀcarbon bond followed by βꢀhydride elimination would
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result in deuterium exchange of all olefinic hydrogens. This similar deuterium exchange was also
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observed for both cis- and trans-stilbene (see Figure S2 in the Supporting Information).
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aAlkyne (0.2 mmol, 0.2 M). H2 and D2 were generated ex situ from Zn (3.4 mmol) and HCl or DCl (6 M, 1 mL).
All yields refer to isolated material; the numbers in square brackets indicate the amount of deuterium
incorporation in percentage.
Scheme 2. Reduction and deuterium labeling of terminal alkynesa
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In order to show the importance of the developed reaction conditions, we applied the transꢀselective
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reduction conditions to the synthesis of three biologically relevant compounds (Scheme 3). The Fꢀ
isotope analogue 7a of the βꢀamyloid fibril tracer, fluorobetaben,14 and its D2ꢀisotope derivative 7aꢀd2
were prepared in a 76% and 73% isolated yield, resp. from the transꢀhydrogenation of the
corresponding alkyne. Double transꢀselective reductions were examined with substrates possessing two
internal alkynes. Hence, for another class of Aβꢀplaque ligands, based on the FSB structure,15
compounds 7bꢀd2, 7c and 7cꢀd2 could be prepared in good yields again with full deuterium
incorporation on both olefin moieties.
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aAlkyne (0.2 mmol), Ru(PPh3)3CO(Cl)H (2.5 mol%), THF (1 mL). H2 and D2 were generated ex situ from Zn
(2.1 mmol) and HCl or DCl (6 M, 1 mL). Stirred at 45 °C for 18 h. bDeuterium incorporation >95% according to
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c
the H NMR spectrum. Alkyne (0.2 mmol), Ru(PPh3)3CO(Cl)H (2.5 mol%), toluene (1 mL). D2 and H2 were
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generated ex situ from Zn (2.1 mmol) and DCl or HCl (6 M, 1 mL). Stirred at 90 °C for 18 h.
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Scheme 3. Synthesis of Aβ tracers Fluorbetaben 7a, FSBꢀanalogs 7b and 7ca
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Next, it was decided to test the transꢀselective Ruꢀhydride catalyst under hydrogen transfer
conditions using formic acid as the hydrogen donor. A continuous flow setup was constructed towards
this purpose with the Ruꢀcatalyst being immobilized on styrene supported triphenylphosphine beads
loaded in a packed bed reactor.16 Due to low solubility of the Ru(PPh3)3CO(Cl)H complex, its
diphenylacetylene added derivative, previously prepared by the group of Santos, was prepared and
loaded onto the modified styrene beads.17 The styrene beads carrying the catalyst precursor were next
placed in a packed bed reactor. Flushing the catalyst bound packed bed with a 2% formic acid solution
in toluene at 90 °C successfully expelled transꢀstilbene rendering the active phosphine coordinated Ruꢀ
hydride catalyst.11 For the reaction setup, toluene was pumped continuously through the flow reactor
while a mixture of diarylꢀalkyne (0.2 M) and formic acid (1.2 M) in toluene (9 mL in total) was loaded
onto a 10 mL sample loop prior to being passed through the heated packed bed reactor (Scheme 4).
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Scheme 4. Selective transꢀhydrogenations in continuous flow.
Immediately, this system turned out to selectively reduce diphenylacetylene to trans-stilbene and
only a short optimization was required to obtain the desired product 2 in a quantitative yield.11 The
retention time of the transformation was successfully lowered to 10 minutes when performing the
transfer hydrogenation at 110 °C or 115 °C. Besides diphenylacetylene, 7 other diarylacetylene
derivatives were tested the results of which are shown in Scheme 4. Given that the ruthenium catalyst
remains immobilized there was no need for purification of the obtained products resulting in nearꢀ
quantitative isolated yields for all entries (2b, 7aꢀf).18 Compound 7a was isolated along with 10% of
the cisꢀisomer indicating that somewhat longer retention time is required for this particular entry. Also
one example of a heteroaromatic thiophene derived acetylene proved reactive under the conditions with
an excellent 96% isolated yield (Compound 7d).
In conclusion, a mild and efficient Ruꢀcatalyzed transꢀselective hydrogenation of alkynes has been
developed applying a commercially available Ru–hydride complex in an operationally simple twoꢀ
chamber reactor with ex-situ generated hydrogen or deuterium. A variety of functional groups could be
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tolerated under the catalytic conditions, even reducible groups, such as nitro, cyano, halides and
amides. The developed conditions could be applied for the reduction and deuterium labeling of
terminal alkynes, providing simple access to styrenes. The method was applied in the synthesis of
compounds relevant for βꢀamyloid fibril detection, which have relevance for diagnostic tests for
Alzheimer’s disease. Finally, the method was extrapolated to a hydrogen transfer protocol in a
continuous flow setup with the active ruthenium hydride being immobilized on triphenylphosphine
modified styrene beads. A retention time of only 10 minutes was required under continuous flow
conditions affording the desired compounds in near quantitative yields and with the same high
selectivity for the trans isomer.
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Associated Content
The supporting information is available free of charge. Optimization tables, procedures and 1H, 13C, 19F
NMR spectra for all produced compounds.
Author Information
Corresponding author email: lindhardt@eng.au.dk
Notes
The authors declare the following competing financial interest: Anders T. Lindhardt and Troels
Skrydstrup are coꢀowners of SyTracks Aps, which commercializes the twoꢀchamber technology.
Acknowledgements
We are deeply appreciative of the generous financial support from the Danish National Research
Foundation, (grant no. DNRF118), the Villum Foundation, Programme Commission on Strategic
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Growth Technologies, Innovation Fund Denmark (0603ꢀ00439B), H. Lundbeck A/S, the Danish
Council for Independent Research: Technology and Production Sciences, the Carlsberg Foundation, the
Lundbeck Foundation and Aarhus University for generous financial support of this work.
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References
1 (a) Cirla, A.; Mann, J. Nat. Prod. Rep. 2003, 20, 558ꢀ564. (b) Tron, G.C.; Pirali, T.; Sorba, G.;
Pagliai, F.; Busacca, S.; Genazzani, A. A. J. Med. Chem. 2006, 49, 3033ꢀ3044. (c) Baur, J. A.;
Sinclair, D. A. Nat. Rev. Drug Discovery 2006, 5, 493ꢀ506. (d) Ager D. J. in Handbook for
Homogeneous Hydrogenation, Vol. 2, 1st ed. (Eds.: J. G. de Vries, C. J. Elsevier), WileyꢀVCH,
Weinheim, 2007, p.745.
2 (a) Lindlar, H. Helv. Chim. Acta 1952, 35, 446ꢀ450. (b) Lindlar, H.; Dubuis, R. Org. Synth. 1966, 46,
89ꢀ91.
3 Pasto, D. J. in Comprehensive Organic Synthesis Vol. 8 (Eds.: B. M. Trrost, I. Flemming), Pergamon,
Oxford, 1991, p. 471.
4 (a) Lie, J.; Hua, R. Chem. Eur. J. 2011, 17, 8462ꢀ8465. (b) Chen, T.; Xiao, J.; Zhou, Y.; Yin, S.; Han,
L.ꢀB. J. Organomet. Chem. 2014, 51ꢀ54. (c) Richmond, E.; Moran, J. J. Org. Chem. 2015, 80, 6922ꢀ
6929. (d) Shen, R.; Chen, T.; Zhao, Y.; Qiu, R.; Yin, S.; Wang, X.; Goto, M.; Han, L.ꢀB. J. Am. Chem.
Soc. 2011, 133, 17037ꢀ17044. (e) Musa, S.; Ghosh, A.; Vaccaro, L.; Ackermann, L.; Gelman, D. Adv.
Synth. Catal. 2015, 357, 2351ꢀ2357. (e) Frihed, T. G.; Fürstner, A. Bull. Chem. Soc. Jpn. 2016, 89,
135ꢀ160. (f) Fuchs, M.; Fürstner, A. Angew. Chem. Int. Ed. 2015, 54, 3978ꢀ3982.
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2
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5
6
7
8
9
5 (a) Schabel, T.; Belger, C.; Plietker, B. Org. Lett. 2013, 15, 2858ꢀ2861. (b) Chen, Z.; Luo, M.; Wen,
Y.; Luo, G.; Liu, L. Org. Lett. 2014, 16, 3020ꢀ3023. (c) Shirakawa, E.; Otsuka, H.; Hayashi, T. Chem.
Commun. 2005, 47, 5885ꢀ5886.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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50
51
52
53
54
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56
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58
59
60
6 (a) Trost, B. M.; Ball, Z. T.; Jöge, T. J. Am. Chem. Soc. 2002, 124, 7922ꢀ7923. (b) Trost, B. M.; Ball,
Z. T. J. Am. Chem. Soc. 2005, 127, 17644ꢀ17655. (c) Trost, B. M.; Machecek, M. R.; Ball, Z. T. Org.
Lett. 2003, 5, 1895ꢀ1898. (d) Trost, B. M.; Ball, Z. T. Synthesis 2005, 853ꢀ887.
7 a) Radkowski, K.; Sundararaju, B.; Fürstner, A. Angew. Chem. Int. Ed. 2013, 52, 355ꢀ360. (b)
Leutzsch, M.; Wolf, L. M.; Gupta, P.; Fuchs, M.; Thiel, W.; Farès, C.; Fürstner, A. Angew. Chem. Int.
Ed. 2015, 54, 12431ꢀ12436.
8 Srimani, D.; DiskinꢀPosner, Y.; BenꢀDavid, Y.; Milstein, D. Angew. Chem. Int. Ed. 2013, 52, 14131ꢀ
14134.
9 (a) Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.; Lupp, D.; Skrydstrup, T. J. Am.
Chem. Soc. 2011, 133, 6061ꢀ6071. (b) Friis, S. D.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J.
Am. Chem. Soc. 2011, 133, 18114ꢀ18117. (c) Lescot, C.; Nielsen, D. U.; Makarov, I. S.; Lindhardt, A.
T.; Daasbjerg, K.; Skrydstrup, T. J. Am. Chem. Soc. 2014, 136, 6142ꢀ6147.
10 Modvig, A.; Andersen, T. L.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J. Org. Chem. 2014,
79, 5861ꢀ5868.
11 The group of Plietker recently reported a transꢀselective alkyne reduction, based on the same
Ru(PPh3)3CO(Cl)H catalyst precursor (see ref 5a). However, their system utilized in situ formation of
hydrogen generated by the reaction of metallic zinc with water. Furthermore, the system required the
addition of 10 mol % of a CuI coꢀcatalyst as well as a reaction temperature of 100 oC. Although being
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a mild method for alkyne reductions, the in situ hydrogen generation results in a decreased functional
group tolerance as seen from competing reduction of functionalities such as the nitro group.
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12 See Electronic Supporting Information for further details.
13 (a) Yabe, Y.; Sawama, Y.; Monguchi, Y.; Sajiki, H. Chem. Eur. J. 2013, 19, 484ꢀ488. (b) Weinhöfer,
G.; Westerhaus, F. A.; Jagadeesh, R. V.; Junge, K.; Junge, H.; Beller, M. Chem. Commun. 2012, 48,
4827ꢀ4829. (c) Tse, S. K. S.; Xue, P.; Lin, Z.; Jia, G. Adv. Synth. Catal. 2010, 352, 1512ꢀ1522.
14 Ong, K.; Villemagne, V. L.; BaharꢀFuchs, A.; Lamb, F.; Chételat, G.; Raniga, P.; Mulligan, R. S.;
Salvado, O.; Putz, B.; Roth, K.; Masters, C. L.; Reininger, C. B.; Rowe, C. C. Alzheimer’s Res. Ther.
2013, 5. 1ꢀ11.
15 Nabuurs, R. J. A.; Kapoerchan, V. V.; Metaxas, A.; de Jongh, S.; de Backer, M.; Welling, M. M.;
Jiskoot, W.; Windhorst, A. D.; Overkleeft, H. S.; van Buchem, M. A.; Overhand, M.; van der Weerd,
L. Bioorg. Med. Chem. 2014, 22, 2469ꢀ2481.
16 For selected examples on hydrogenations and transfer hydrogenations in continuous flow, see: (a)
Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Org. Lett. 2013, 15, 2278ꢀ2281. (b) O´Brian, M.; Taylor,
N.; Polysos, A.; Baxendale, I. R.; Ley, S. V. Chem. Sci. 2011, 2, 1250ꢀ1257. (c) Saaby, S.; Knudsen, K.
R.; Ladlow, M.; Ley, S. V. Chem. Commun. 2005, 2, 2909ꢀ2911. (d) Hattori, T.; Tsubone, A.; Sawama,
Y.; Monguchi, Y.; Sajiki, H. Tetrahedron 2014, 70, 4790ꢀ4798. (e) Kleinke, A. S.; Jaminson, T. F.
Org. Lett. 2013, 15, 710ꢀ713. (f) Cossar, P. J.; Hizartzidis, L.; Simone, M. I.; McCluskey, Gordon, C.
P. Org. Biomol. Chem.2015, 13, 7119ꢀ7130. (g) Mallia, C. J.; Baxendale, I. R. Org. Process, Res. Dev.
2016, 20, 327ꢀ360.
17 Torres, M. R.; Vegas, A.; Santos, A.; Ros, J. J. Organomet. Chem. 1986, 309, 169ꢀ177.
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18 Application of a packed bed setup retains the catalyst in the reactor. This allows the same amount of
catalyst to be reused for numerous experiments indicating a high stability and reusability of developed
matrixꢀloaded catalyst.
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