DOI: 10.1002/cctc.201500821
Communications
Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation
of Propargylic Ketones
Andrey Shatskiy, Tove Kivijärvi, Helena Lundberg, Fredrik Tinnis, and Hans Adolfsson*[a]
The asymmetric transfer hydrogenation of a,b-propargyl ke-
tones catalyzed by an in situ formed ruthenium–hydroxyamide
complex was explored. The acetylenic alcohols were isolated in
good to excellent yields with excellent ee values (typically
>90%) after short reaction times at room temperature.
the hydrogen donor.[23] Herein, we show that propargylic ke-
tones can successfully be added to the substrate scope of this
class of ATH catalysts. Excellent yields and enantioselectivities
of propargylic alcohols were obtained at room temperature
with the use of low catalyst loadings of the [Ru(p-cym)Cl2]2
(p-cym=p-cymene) complex in combination with ligand
(S,S)-L1 (Figure 1).
Enantiomerically pure propargylic alcohols are valuable and
versatile synthetic building blocks that are widely used in or-
ganic synthesis.[1] These compounds can be transformed into,
for example, asymmetric allenes[2] and enantiomerically pure
aliphatic and allylic alcohols.[3,4] Natural products such as pros-
taglandins,[5] macrolides,[6] pheromones,[7] and musclides[8] have
been produced by utilizing homochiral propargylic alcohols as
key elements in their synthesis, and these particular building
blocks are frequently employed in the formation of cyclic and
polycyclic compounds with several stereogenic centers.[9]
Enantiomerically enriched propargylic alcohols can be
formed by different synthetic methods.[1,10] Asymmetric addi-
tion of acetylenes to carbonyls is a common strategy,[3b,11] and
asymmetric addition of carbon nucleophiles to alkynals[12] and
alkynones[13] has also been reported. Kinetic resolution[14] and
dynamic kinetic resolution[15] of racemic propargylic alcohols
constitute two other approaches. Asymmetric propargylic alco-
hols are also available by reduction of the corresponding ke-
tones. This family of methods spans from stoichiometric reduc-
tions, for example, by using chiral boron reagents[16] and alumi-
num hydride reagents,[7b,17] to catalytic protocols with en-
zymes[18] or chiral phosphoric acids.[19] In addition, propargylic
alcohols are available through ruthenium-catalyzed asymmetric
hydrogenation and asymmetric transfer hydrogenation (ATH).
However, to date, only a handful of catalytic protocols are
known for these transformations.[20,21] Further development of
milder and more cost-efficient methods in this field is therefore
of great value for the chemical community.
The initial screening was performed
by using 4-phenyl-3-butyn-2-one (1a)
as a model substrate and by employing
conditions previously developed for the
asymmetric transfer hydrogenation of
ketones.[22f] Using the ruthenium cata-
lyst (2 mol%), it was found that the re-
Figure 1. Hydroxy-
amide ligand (S,S)-L1
derived from l-alanine.
action mixture needed to be diluted
from 0.2 to 0.01m in a mixture of THF/
iPrOH (1:1) to reach a reasonable yield
of the propargylic alcohol (Table 1,
entry 1). Further evaluation of solvent mixtures and concentra-
tions revealed that high yield and enantioselectivity of the
model substrate alcohol was obtained after only 5 min at
room temperature by using a mixture of iPrOH/toluene (1:1) at
a concentration of 0.1m (Table 1, entry 6). Performing the reac-
tion in isopropanol without a co-solvent resulted in a reaction
that was slower than that performed in a 1:1 mixture with tol-
uene at the same reactant concentration (Table 1, entries 3 and
6). No product was formed if the reaction was conducted with-
out the catalyst and ligand present with all other conditions
identical. Instead, substrate decomposition was seen to some
Table 1. Influence of solvent and ketone concentration.[a]
We previously reported the use of transition-metal catalysts
in combination with amino acid derived hydroxyamide ligands
for the asymmetric transfer hydrogenation of aryl alkyl ketones
by using alcohols as terminal reductants.[22] We also demon-
strated that some of our amino acid based catalytic systems
could mediate the enantioselective reduction of ketones, in-
cluding an aliphatic ketone, in a water system with formate as
Entry Solvent
Concentration Time Conversion[b] ee[c]
[m]
[min] [%]
[%]
1
2
3
4
5
6
7
8
iPrOH/THF (1:1)
iPrOH/THF (1:1)
iPrOH
iPrOH/hexane (1:1) 0.05
iPrOH/toluene (1:1) 0.05
iPrOH/toluene (1:1) 0.1
0.01
0.05
0.05
30
120
60
60
15
5
full
51
71
17
full
full
full
–
97
95
n.d.
n.d.
98
98
97
n.d.
iPrOH/PhCl (1:1)
iPrOH/tBuOH (1:1)
0.1
0.1
30
60
[a] A. Shatskiy, T. Kivijärvi, Dr. H. Lundberg, Dr. F. Tinnis, Prof. H. Adolfsson
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University
[a] For the experimental procedure, see the Supporting Information.
[b] Conversion was determined by 1H NMR spectroscopy. [c] The enantio-
selectivity was determined by HPLC on a chiral stationary phase (Chiralcel
OB column). n.d.=not determined.
106 91 Stockholm (Sweden)
Supporting Information for this article is available on the WWW under
ChemCatChem 2015, 7, 3818 – 3821
3818
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