Chemoselective Continuous Ru-Catalyzed Hydrogen-Transfer Oppenauer-Type Oxidation of Secondary Alcohols

Article abstract of DOI:10.1021/acs.oprd.7b00190

A continuous flow method for the selective oxidation of secondary alcohols is reported. The method is based on an Oppenauer-type ruthenium-catalyzed hydrogen-transfer process that uses acetone as both solvent and oxidant. The process utilizes a low loading (1 mol%) of the commercially available ruthenium catalyst [Ru(p-cymene)Cl₂]₂ and triethylamine as a base and can be successfully applied to a range of different substrates, with a good level of functional group tolerance.

Full text of DOI:10.1021/acs.oprd.7b00190

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Communication
Chemoselective Continuous Ru-Catalyzed Hydrogen-
transfer Oppenauer-type Oxidation of Secondary Alcohols
Ricardo Labes, Claudio Battilocchio, Carlos Mateos, Graham Cumming,
Oscar de Frutos, Juan A. Rincon, Kellie Binder, and Steven V Ley
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00190 • Publication Date (Web): 04 Aug 2017
Downloaded from http://pubs.acs.org on August 5, 2017
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Chemoselective Continuous RuꢀCatalyzed
Hydrogenꢀtransfer Oppenauerꢀtype Oxidation of
Secondary Alcohols
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Ricardo Labes,† Claudio Battilocchio,† Carlos Mateos,‡* Graham R. Cumming,‡ Oscar de
Frutos,‡ Juan A. Rincón,‡ Kellie Binder,§ Steven V. Ley.†*
† Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield
Road, Cambridge, CB2 1EW, U.K.
‡ Centro de Investigación Lilly S.A., Avda. de la Industria 30, AlcobendasꢀMadrid 28108, Spain.
§
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW,
U.K.
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KEYWORDS: Continuous processing, Hydrogen transfer, Homogeneous catalysis, Oxidation,
Ruthenium catalysis.
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ABSTRACT: A continuous flow method for the selective oxidation of secondary alcohols is
reported. The method is based on an Oppenauerꢀtype rutheniumꢀcatalyzed hydrogenꢀtransfer
process that uses acetone as both solvent and oxidant. The process utilizes a low loading (1
mol%) of the commercially available ruthenium catalyst [Ru(pꢀcymene)Cl2]2, triethylamine as
base, and can be successfully applied to a range of different substrates, with a reasonable level of
functional group tolerance.
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The oxidation of alcohols is a fundamental transformation in chemical synthesis and many
protocols have been developed over the years to afford different product outcomes and
functional group tolerances. However, the development of chemoselective, safe and practical
oxidation methods continue to be of major interest in the community.1–4
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Catalytic oxidation is particularly relevant for large scale industrial processes and, despite the
outstanding progress, further development is needed if we are to respond to contemporary
environmental challenges and with limited resources.1,5
Hydrogen transfer methods constitute an attractive approach for many synthetic
transformations.6–8 Among these, reduction processes are more well established.9–17 Hydrogen
transfer oxidation methods have also evolved, with the development of new catalysts, employing
aqueous media, supported catalysts and in the absence of hydrogen acceptors.18–25 Most notably,
Bäckvall’s group has implemented procedures for hydrogen transfer oxidation employing
commercial catalysts, and a base, to achieve high yields, and with good functional group
compatibility.26,27
Furthermore the advantages of continuous flow methods applied to research and development
programs are now well recognized in academia and industry.28–38
Following our interest in redox reactions using continuous flow methods,39–42 we report here
efforts to develop a continuous rutheniumꢀcatalyzed hydrogenꢀtransfer oxidation process.
We reasoned that we needed to combine the safety and selectivity of hydrogen transfer oxidation
and continuous flow systems to deliver a method with broad application. For the work, a
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minimal system was assembled comprising a pump, heated coil and backpressure regulator
(BPR), with acetone as the chosen proton acceptor to facilitate downstream processing. Steady
state of the system was followed using an inꢀline UVꢀVis detector.43 The continuous system that
was developed facilitates work beyond normal solvent reflux temperatures employed in other
studies, and avoids any formation of aldol byꢀproducts.
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Dichloro(pꢀcymene)ruthenium(II) dimer was selected as the catalyst to facilitate the oxidation of
alcohols. [Ru(pꢀcymene)Cl2]2 was favored as it is commercially available, airꢀstable, and
relatively inexpensive when compared to other precious metal catalysts.
Previous reports demonstrate that the addition of a base improves the oxidative catalytic
cycle.27,44,45 To avoid the use of inorganic bases, which have poor solubility in acetone, and
might compromise downstream processes, we opted to use triethylamine. Triethylamine is liquid,
soluble and can be easily removed by evaporation, and gave us better yields, especially when
compared to N,Nꢀdiisopropylethylamine (see ESI). The initial optimization (see ESI) provided a
method whereby a 0.1 M solution of the alcohol in acetone, 1 mol% of the ruthenium catalyst
and 2 equivalents of triethylamine were passed through a 40 mL heated coil (1/8″ o.d. stainlessꢀ
steel) reactor (ESI Figure S1) at 1 mL/min. This same protocol was then applied to a variety of
other alcohols including aromatic, aliphatic and allylic examples (Table 1).
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Table 1. Substrate scope for the ruthenium catalyzed hydrogen transfer oxidation of alcohols
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T (°C)
1 mL/min
OH
R 1
O
20 bar
R
R
R 1
8
9
40 mL
SS 1/8"
0.1 M in Acetone
[Ru(p-cymene)Cl2]2 (1 mol%)
Et3N (2 equiv.)
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Entry
Substrate
Temperature (°C)
Yielda(b)
91
1
2
100
150
97(95)
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4
5
6
100
150
100
150
80
OH
N
80(74)
71
OH
97 (92)
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100
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100
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99(95)
97(95)c
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100
150
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99(97)
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150
76(74)
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150
150
99(98)
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150
150
0
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18
19
100
150
50d
64(60)d
20
150
58
21
150
60
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150
77(75)d
H
H
H
HO
H
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24
100
150
75e
84(79)e
O
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26
150
150
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N
O
HO
40f
OH
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150
14
79f
N
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150
99(96)g
OH
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100
150
6
12
Cl
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33
100
150
50
72f
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100
100
60 h
HO
OH
0
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aYield determined by 1H NMR integration against internal standard (1,3,5ꢀtrimethoxybenzene).
c
d
bIsolated yields. Solution prepared in a mixture 9:1 acetone/toluene. Solution prepared in a
e
f
mixture 8:2 acetone/toluene. A 0.05M solution in a mixture 1:1 acetone/toluene was used. 5
g
mol% of catalyst used. In a small scale experiment we have directly compared the flow
procedure to batch, as expected we obtained a comparable isolated yield.46 hYield of ketone, no
aldehyde observed by 1H NMR.
The reaction proved to be compatible with double bonds, heterocycles and esters. Pleasingly,
very hindered alcohols could be successfully oxidized, such as exoꢀnorborneol (entries 3 & 4)
and adamanthanol (entries 18 & 19). 5αꢀCholestanꢀ3βꢀol and terfenadine further exemplified the
application of the method to natural product and active pharmaceutical ingredient substrates
(entries 22 & 23 respectively). While nitrogenꢀcontaining substrates were successfully oxidized
(e.g. entries 5 & 13), NꢀBocꢀLꢀprolinol and a pyridine derivative (entries 25ꢀ28) required a
higher catalyst loading to provide good yields of products. Reaction outputs were generally very
clean, being composed of unreacted starting material and product. The system demonstrated high
selectivity towards secondary alcohols over primary alcohols. For instance, pꢀchlorobenzyl
alcohol provided only 12% of product at 150 °C (entry 31), while its secondary analogue was
readily oxidized (entry 29). So when (R)ꢀ1ꢀphenylꢀ1,3ꢀpropanediol was submitted to the reactor
system, only the secondary position was oxidized, showing excellent chemoselectivity (entry
34). Despite the lower reactivity of geraniol (entries 32 & 33), it could be oxidized by increasing
the catalyst loading at 150 °C. Not surprisingly, strongly chelating substrates such as 1,2ꢀ
octanediol (entry 35) failed to oxidize under a range of different reaction conditions. When (R)ꢀ
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1ꢀ(2ꢀbromophenyl)ethanꢀ1ꢀol (entry 16) was submitted to the system, starting material was
recovered, while the para substituted analogue (entry 15) was readily converted to the
corresponding ketone. This can be rationalized as the alpha substituted can hinder the hydroxyl
group, differently from the para substituted analogue.
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To further evaluate the chemoselectivity of the method a mixture of octanꢀ2ꢀol and nonanꢀ1ꢀol
was reacted under standard conditions. In this experiment, more than 98% of the secondary
alcohol was oxidized while less than 3% of the aldehyde was detected (Scheme 1).
Scheme 1. Oxidation of a mixture of primary and secondary alcohols
O
OH
150 °C
98%
<3%
1 mL/min
20 bar
+
OH
+
O
40 mL
SS 1/8"
H
0.1 M in Acetone
[Ru(p-cymene)Cl 2]2 (1 mol%)
Et3N (2 equiv.)
The scalability of the system was rapidly evaluated using 2ꢀoctanol as a model substrate (Table
S2, ESI). By increasing concentration of the substrate and flow rate it was possible to achieve a
productivity of 34.6 g/h of 2ꢀoctanone (Scheme 2). At 10 mL/min a second coil was used to cool
the reaction mixture and prevent it from boiling after the BPR. The reaction was operated
continuously for 4 hours with no issues, such as clogging, being observed. When we attempted to
use the system using even higher concentration and catalyst load, blockage occurred after 40
minutes (Table S2, ESI).
Scheme 2. Scaleꢀup experiment for the oxidation of 2ꢀoctanol
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150 °C
10 mL/min
RT
OH
O
20 bar
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7
8
9
40 mL 5 mL
SS 1/8"
90%
0.5 M in Acetone
[Ru(p-cymene)Cl2]2 (0.5 mol%)
34.6 g/h
138.4 g after 4 h
1.1 mol
Et3N (2 equiv.)
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Downstream processing was incorporated with the reaction output (28 mL) delivered to a flask
containing QuadraSilTMꢀMP (1.94 g, 1.2 mmol/g) to remove the soluble residual Ru content from
the reaction stream. After filtration and solvent removal, effective removal of Ru was shown by
ICPꢀMS data (1.19 ppm) delivering the product with high level of purity.
We were also interested in understanding the role of the Ru catalyst, as previous reports had
shown that Ruꢀcatalyzed hydrogen transfer reactions can proceed through different routes.47
Ruthenium dichloride catalysts are understood to follow a mono or diꢀhydric pathway in both
dehydrogenation and hydrogenation reaction. Sasson argued that Ru0 nanoparticles are the real
catalyst for the hydrogen transfer reductions using [(C6H5)3P]3RuCl2.48 Similarly to Sasson’s
report, our process was characterized by a color change during the reaction progression (from red
to black), with the eventual deposition of particles after time (see ESI). We also noticed that the
formation of Ru particles was directly related to the temperature of the system. To help
understand the nature of the catalyst, mercury poisoning experiments were performed48,49 and no
difference in catalytic activity was observed. These results support the proposal of a soluble
catalyst, and that the particles observed are formed as a byꢀproduct from the redox process.
Elemental analysis of the black particles showed 3ꢀ6% of carbon and 1%< for both hydrogen and
nitrogen. TEM analysis (see ESI) showed the particles are highly aggregated with an average
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diameter of diameter of 2.35697 nm (+0.13) and particle distribution of 5.36%. Measurement of
lattice fringes are in accordance with the values expected for ruthenium.
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In summary, we have developed a continuous flow system for the rutheniumꢀcatalyzed
hydrogenꢀtransfer oxidation of mainly secondary alcohols. The method utilizes 1 mol% of the
commercially available catalyst [Ru(pꢀcymene)Cl2]2 and triethylamine as base. The process was
successfully applied to a range of different substrates, and represents a notable improvement on
our previous related oxidation studies.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Detailed experimental data and characterization of compounds.
Additional data is available from the University of Cambridge Data Repository
website: https://doi.org/10.17863/CAM.10216
AUTHOR INFORMATION
Corresponding Author
* Dr Carlos Mateos eꢀmail: c.mateos@lilly.com
* Prof. Steven V. Ley email: svl1000@cam.ac.uk
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
The authors are grateful to Eli Lilly & Co. (RL) and the EPSRC (SVL, grants EP/K009494/1,
EP/M004120/1 and EP/K039520/1) for financial support. This work was supported by Eli Lilly
& Co. through the Lilly Research Award Program (LRAP).
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