A mild chemoselective Ru-catalyzed reduction of alkynes, ketones, and nitro compounds

Article abstract of DOI:10.1021/ol401185t

The chemoselective reduction of alkyne, ketones, or nitro groups using (Ph₃P)₃RuCl₂ as an inexpensive catalyst and Zn/water as a stoichiometric reductant is reported. Depending on the nature of the additive and the temperature, good chemoselectivities were observed allowing, e.g., for the selective reduction of a nitro group in the presence of a ketone or an alkyne.

Full text of DOI:10.1021/ol401185t

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
A Mild Chemoselective Ru-Catalyzed
Reduction of Alkynes, Ketones,
and Nitro Compounds
Tobias Schabel,† Christian Belger,† and Bernd Plietker*
€
Institut fu€r Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55,
DE-70569 Stuttgart, Germany
bernd.plietker@oc.uni-stuttgart.de
Received April 26, 2013
ABSTRACT
The chemoselective reduction of alkyne, ketones, or nitro groups using (Ph3P)3RuCl2 as an inexpensive catalyst and Zn/water as a stoichiometric
reductant is reported. Depending on the nature of the additive and the temperature, good chemoselectivities were observed allowing, e.g., for the
selective reduction of a nitro group in the presence of a ketone or an alkyne.
The development of environmentally benign catalytic
reactions is without a doubt a focus of current chemical
research.1 Apart from lowering the energy consumption of
a chemical transformation using catalysts, the chemose-
lective transformation of only one out of many functional
groups within a more complex molecular framework
allows the reduction of byproducts (and hence waste)
and streamlines synthetic pathways by eliminating tedious
protecting group operations.2 Within the catalytic portfolio
hydrogenations play a pivotal role. Although well-estab-
lished and performed on multi-ton scale this type of chemical
reaction suffers from different problems such as chemoselec-
tivity. To date only three protocols for the chemoselective
reduction of, e.g., a nitro group in the presence of a carbonyl
group or an alkyne using either hydrazine3 or formic
acid/Et3N4 as a stoichiometric reductant has been devel-
oped. Recently, our group and others became interested in
transition-metal catalyzed reduction of alkynes under
transfer hydrogenation conditions using formic acid as a
H2-surrogate.5 In furtherance of these investigations we
were wondering whether it could be possible to develop
a protocol that addresses two important questions: (a) Is
it possible to develop a protocol in which H2O, the
most stable and abundant H2-surrogate, is employed in a
(4) (a) Wienhoefer, G.; Sorribes, I.; Boddien, A.; Westerhaus, F.;
Junge, K.; Junge, H.; Llusar, R.; Beller, M. J. Am. Chem. Soc. 2011, 133,
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12875–12879. (b) Sorribes, I.; Wienhofer, G.; Vicent, C.; Junge, K.;
Llusar, R.; Beller, M. Angew. Chem., Int. Ed. 2012, 51, 7794–7798.
(5) (a) Belger, C.; Neisius, N. M.; Plietker, B. Chem.;Eur. J. 2010,
16, 12214–12220. (b) Gao, Y.; Jennings, M. C.; Puddephatt, R. J. Can. J.
Chem. 2001, 79, 915–921. (c) Shen, R.; Chen, T.; Zhao, Y.; Qiu, R.;
Zhou, Y.; Yin, S.; Wang, X.; Goto, M.; Han, L.-B. J. Am. Chem. Soc.
2011, 133, 17037–17044. (d) Li, J.; Hua, R.; Liu, T. J. Org. Chem. 2010,
75, 2966–2970.
(6) (a) Sato, T.; Watanabe, S.; Kiuchi, H.; Oi, S.; Inoue, Y. Tetra-
hedron Lett. 2006, 47, 7703–7705. (b) Mukhopadhyay, S.; Rothenberg,
G.; Wiener, H.; Sasson, Y. New J. Chem. 2000, 24, 305–308. (c) Barrios-
Francisco, R.; Garcia, J. J. Inorg. Chem. 2009, 48, 386–393. (d) Campana,
A. G.; Estevez, R. E.; Fuentes, N.; Robles, R.; Cuerva, J. M.; Bunuel, E.;
Cardenas, D.; Oltra, J. E. Org. Lett. 2007, 9, 2195–2198.
† Both authors contributed equally.
(1) Ahluwalia, V. K. Green Chemistry: Enviromentally Benign Reac-
tions; CRC Press: 2007.
(2) Sarmah, P. P.; Dutta, D. K. Green Chem. 2012, 14, 1086.
€
(3) Jagadeesh, R. V.; Wienhofer, G.; Westerhaus, F. A.; Surkus,
A.-E.; Pohl, M.-M.; Junge, H.; Junge, K.; Beller, M. Chem. Commun.
2011, 47, 10972–10974.
r
10.1021/ol401185t
XXXX American Chemical Society

stoichiometric manner?6 and (b) Can we address the open
question of chemoselectivity in transition-metal catalyzed
hydrogen transfer reactions by utilizing addivitives? Here,
we present the results of our studies which led to the
discovery of a Ru-catalyzed reduction by which, depend-
ingonthe additiveand temperature, alkynesare reduced to
olefins in the presence of carbonyl groups and vice versa.
Stoichiometric amounts of Zn-powder and water are used
as a hydrogen source.
Table 1. Ru-Catalyzed Semireduction of Alkynes: System
Developmenta
At the outset of our studies we choose the reduction of
diphenylacetylene as a starting point and evaluated the
influence of solvent, catalyst, and temperature (Table 1).
Commercially available RuCl2(Ph3P)3 (1) in dioxane in the
presence of only 8 equiv of water showed a promising
conversion rate in favor of the Z-configured substitution
product (entry 1, Table 1). However at a certain point the
conversion stopped. In order to circumvent problems
associated with the passivation of the Zn-surface, catalytic
amounts of CuI were added.7 This additive had a beneficial
influence on both reaction rate and Z/E-selectivity. The
desired Z-stilbene (Z-3) was obtained in almost quantita-
tive conversion and a Z/E-selectivity of >8:1 (entry 7,
Table 1). Various Ru(þII)-complexes were subsequently
screened for their catalytic activities (entries 10ꢀ22,
Table 1). Strong ligand and anion effects were observed.
Whereas three basic ligands allow for good to excellent
conversion rates, complexes that are coordinated by four
N- or P-ligands turned out to be nonactive. Apart from
complex 1 Murai’s catalyst 7 showed good reactivity;
however it led to the formation of the E-configured olefin
predominantely. Complex 1 on the other hand proved to
be more active in the reduction and less active for π-bond
isomerization. The isomerization was complete within 36 h
(entry 7, Table 1). For reasons of practicality and with
regard to the stereodivergence option, we chose the readily
available (Ph3P)3RuCl2 as the catalyst for this study.
Importantly, no conversion was observed in the absence
of the Ru-catalyst (entries 23 and 24, Table 1).
a The reactions were performed on a 0.5-mmol scale using 2.5 mol %
Ru cat. at 100 °C in dry solvent (1 mL) for 16 h under a N2 atmosphere.
b Catalyst structures shown above. c Determined by 1H NMR or GC
integration. d E/Z selectivity and yield after a reaction time of 36 h are
given in parentheses.
Having in hand a practical catalytic protocol for the
semireduction of alkynes, we subsequently tested the scope
of this transformation using various internal alkynes
(Table 2). The reaction proved to be broadly applicable
toward the reduction ofarylacetylenes. After 36h at100°C
good to excellent E/Z selectivities and yields were obtained
(protocol A, Table 2).
given reaction conditions; however π-bond migration and
hence product mixtures were obtained.8
Functional groups such as amides, esters, alcohols,
halides, and nitriles are compatible with the reaction
conditions (Table 2). In the presence of a nitro group,
however, rapid reduction of the nitro group was observed.
The reduction of the triple bond was significantly slower.
However, in all cases no overreduction to the saturated
CꢀC bond was observed. Stopping the reaction after 16 h
using only 2.5 mol % of catalyst 1 led to the formation of the
desired olefin in good to excellent yields albeit at moderate
to good stereoselectivities in favor of the Z-configured
double bond. Aliphatic alkynes are also reactive under the
The use of Murai’s catalyst (7) led to the direct forma-
tion of the E-configured alkenes within just 16 h (entry 15,
Table 1). However, this protocol proved to be very sensi-
tive toward the functional group as compared to the use of
(Ph3P)3RuCl2 (Table 2). Careful control of E/Z selectivity
vs conversion and time indicated this catalyst to be active
bothfor the reduction tothe Z-configured olefin and for its
isomerization into the thermodynamically more favorable
E-product. The fact that even ketones are not reduced at
100 °C after 36 h attracted our attention. We were wonder-
ing whether we could extend the method to the reduction of
(7) Knochel, P.; Jones, P. Organozinc reagents (A Practical
Approach): Oxford University Press: 1999.
(8) (a) Yue, C. J.; Liu, Y.; He, R. J. Mol. Catal. A 2006, 259, 17–23.
(b) Lastra-Barreira, B.; Crochet, P. Green Chem. 2010, 12, 1311–1314.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Ru-Catalyzed Semireduction of Alkynes
Table 3. Ru-Catalyzed Reduction of Aldehydes/Ketonesa
a All reactions were performed on a 0.5-mmol scale using 2.5 mol %
RuCl2(PPh3)3 (1), 25 mol % KOH powder, 2 equiv of Zn-powder, and 8
equiv of H2O at the given temperature in dry 1,4-dioxane (1 mL) for 16 h
under a N2 atmosphere. b Isolated yields. c Starting from p-nitroaceto-
phenone. Yield of p-aminoacetophenone is given in parentheses. d The
reaction was performed on a 0.5-mmol scale using 5 mol % RuCl2(PPh3)3
(1), 1 equiv of KOH powder, 4 equiv of Zn-powder, and 16 equiv of H2O at
80 °C in dry 1,4-dioxane (1 mL) for 16 h under a N2 atmosphere.
yields of the corresponding alcohols were observed. How-
ever, whereas both aromatic and aliphatic ketones are
suitable substrates, aromatic aldehydes undergo a fast non-
catalytic pinacol-type coupling and proved to be a limitation
of this method.10 In sharp contrast aliphatic aldehydes are
highly reactive and give rise to the expected products in good
to excellent isolated yields. Even an aqueous formalin solu-
tion can be employed giving methanol in high yield (entry 8,
Table 3). Importantly, no conversion was observed in the
absence of catalyst 1. Moreover, nitro groups proved to be
more reactive. Increasing the amount of the Zn powder and
base allowed for a reduction of p-aminoacetophenone to the
corresponding aminoalcohol 29 with formation of significant
amounts of p-aminoacetophenone as the side product
(Table 3, entry 5).
a The reactions were performed on a 0.5-mmol scale using 2.5 mol %
RuCl2(PPh3)3 (1) at 100 °C in dry dioxane (1 mL) for 36 h under a N2
atmosphere (protocol A) or using 2.5 mol % (Ph3P)3Ru(CO)HCl (7) at
100 °C for 36 h under a N2 atmosphere (protocol B). b E/Z selectivity was
determined by 1H NMR or GC integration. c Isolated yields. d Values in
brackets refer to the Z/E selectivity and yields for the same reaction
conditions using 2.5 mol % RuCl2(PPh3)3 (1) and a 16 h reaction time.
carbonyl or nitro groups and were hoping to invert the course
of the chemoselectivity. Since the initial steps within the
reduction of carbonyl and nitro groups are identical we
assumed a transfer of the known literature conditions for
reductive dimerizations of nitro arenes to the corresponding
diazocompounds using a Zn/KOH combination to be
possible.9 Indeed by exchanging the additive from CuI to
KOH and lowering the reaction temperature down to
60ꢀ80 °C, a variety of functionalized ketones and aldehydes
were reduced to the corresponding alcohols (Table 3).
A variety of ketones proved to be reactive under the given
conditions. At temperatures of ∼80 °C good to excellent
Subsequently we extended this method to the reduction
of nitroarenes4,11ꢀ13 (Table 4). Nitro groups are known
(10) (a) Tanaka, K.; Kishigami, S.; Toda, F. J. Org. Chem. 1990, 55,
2981–2983. (b) Oller-Lopez, J. L.; Campana, A. G.; Cuerva, J. M.; Oltra,
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Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Ru-Catalyzed Reduction of Nitro Groupsa
Scheme 1. Ru-Catalyzed Reduction of Nitroso Groups,
Oximes, and Diazobenzene
the organic and inorganic products were separated
by filtration and isolated in almost identical yields.
The filtrates were evaporated, and the crude products
were purified by chromatography. Analysis of the inor-
ganic solids revealed two major aspects: (a) low levels of
ruthenium (4.2ꢀ26.7 ppm) were detected in ICP-MS14
and XRD studies decreasing the probability of colloidal
ruthenium to be formed and active as the catalyst; and (b)
the solids consist of a mixture of zinc, ZnO, and Zn(OH)2
as shown by XRD. These investigations indicate that an
almost quantitative regeneration of the Zn(OH)2 could
be possible.
a All reactions were performed on a 0.5-mmol scale using 2.5 mol %
RuCl2(PPh3)3 (1), 25 mol % KOH powder, 3.3 equiv of Zn-powder, and
8 equiv of H2O at the given temperature in dry 1,4-dioxane (1 mL) for
16 h under a N2 atmosphere. b Isolated yields.
Herein we describe a practical and chemoselective reduc-
tion of alkynes, ketones, and nitro groups using catalytic
amounts of (Ph3P)3RuCl2 and stoichiometric amounts of
zinc/water as the reductant. In the presence of catalytic
amounts of CuI, a selective reduction of alkynes even in the
presence of carbonyl groups was achieved; however switch-
ing the catalytic additive toward KOH led to a full inversion
of the chemoselectivity. Alkynes stay intact, whereas nitro
groups and ketones proved to be reactive.
to be reduced by elemental zinc in the presence of base to
the corresponding nitroso group, oximes, or even diazo-
compounds.9 However, in the presence ofcatalyst1 neither
of these products was observed. Instead a very selective
reduction of the nitro group even in the presence of a
ketone(entry 6, Table 4) or an alkyne (entry 5, Table 4)
was observed. Whereas nitroarenes are reactive under the
given conditions, aliphatic or benzylic nitro groups were
giving no or very low yields (entry 4, Table 4).
In the absence of Ru-catalyst 1 nitrobenzene was reduced
to a mixture of diazobenzene 44 and hydrazobenzene. Aniline
45 however was not detected in the crude mixture. Since
nitroso arenes and aryl hydroxylamines or even diazocom-
pounds are potential intermediates in this multistep reduction
process we subsequently subjected these compounds to the
reaction conditions. Indeed the reduction of 42ꢀ44 under the
standard conditions in the presence of catalyst 1 led to the
formation of aniline 45 in excellent yield (Scheme 1).
Acknowledgment. Financial support by the Landesgra-
€
duiertenstiftung Baden-Wurttemberg (Ph.D. grant for C.B.)
and the Deutsche Forschungsgemeinschaft (SFB 706) is
gratefully acknowledged. We thank Prof. Dr. Elias Klemm
and Dipl.-Chem. Vanessa Scholz (Institute of Technical
Chemistry, University of Stuttgart) for performing XRD
analysis of the Zn-residues.
Supporting Information Available. Full experimental
1
details, spectroscopic data, and copies of H and 13C
Furthermore, the reduction of diphenylacetylene and
acetophenone were carried out on a 10-mmol scale. Both
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Bull. Chem. Soc. Jpn. 1984, 57, 2440–2444. (b) Taleb, A. B.; Jenner, G.
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(b) Crabtree, R. H. Chem. Rev. 2012, 112, 1536–1554. (c) Widegren, J. A.;
Finke, R. G. J. Mol. Catal. A 2003, 198, 317–341.
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX