Tandem α-Alkylation/Asymmetric Transfer Hydrogenation of Acetophenones with Primary Alcohols

Article abstract of DOI:10.1002/ejoc.201403032

Tandem α-alkylation/asymmetric transfer hydrogenation of acetophenones with primary alcohols, mediated by a single ruthenium catalyst, is described. Under optimized reaction conditions and with use of [Ru(p-cymene)Cl₂]₂ in combination with an amino acid hydroxyamide ligand, the chiral secondary alcohol products were isolated in moderate yields and in moderate to good enantiomeric excess (up to 89 % ee). One catalyst - one pot - two reactions. Acetophenones are initially alkylated with primary alcohols by the borrowing hydrogen methodology. The alkylation products are directly converted to enantiomerically enriched secondary alcohols.

Full text of DOI:10.1002/ejoc.201403032

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403032
Tandem α-Alkylation/Asymmetric Transfer Hydrogenation of Acetophenones
with Primary Alcohols
Oleksandr O. Kovalenko,[a] Helena Lundberg,[a] Dennis Hübner,[a] and Hans Adolfsson*[a]
Keywords: Alkylation / Amino acids / Asymmetric catalysis / Reduction / Ruthenium
A tandem α-alkylation/asymmetric transfer hydrogenation of
acetophenones with primary alcohols, mediated by a single
ruthenium catalyst, is described. Under optimized reaction
conditions and with use of [Ru(p-cymene)Cl2]2 in combina-
tion with an amino acid hydroxyamide ligand, the chiral sec-
ondary alcohol products were isolated in moderate yields and
in moderate to good enantiomeric excess (up to 89% ee).
source in the transfer hydrogenation also acts as one of the
reactants.[13]
Introduction
A significant amount of drugs available on the pharma-
ceutical market contain stereocenters, which play important
roles for the bioactivity of these compounds. Certain iso-
mers are simply inactive, like (R)-Ibuprofen; however,
others are harmful, like (R)-Naproxen.[1] Therefore, the de-
velopment of selective methods for the formation of single-
enantiomer drugs is highly important. One example of such
a method is the transition-metal-catalyzed formation of en-
antiomerically enriched secondary alcohols by asymmetric
transfer hydrogenation of ketones, which represents one of
the most common asymmetric reduction methods in mod-
ern organic chemistry.[2] Among the available catalytic sys-
tems, the use of ruthenium-based catalysts have attracted
significant attention due to generally high activity, enabling
low catalyst loadings and mild reaction conditions.[2,3]
The α-alkylation of methyl aryl ketones with primary
alcohols as alkylating agents (Scheme 1), is frequently de-
scribed in the literature with different homo- and hetero-
geneous catalysts based on Ru,[4] Rh,[5] Pd,[6] Os,[7] Ir,[8]
Ni,[9] Cu,[10] as well as Ag–Pd[11] and Ag–Mo[12] mixed-
metal materials. The transformation is a nice example of
the borrowing hydrogen methodology, where the hydrogen
A similar process, where the α-alkylated ketone is re-
duced in the final step to furnish a secondary alcohol, is
also reported in the literature. Shim and co-workers devel-
oped a ruthenium-catalyzed procedure that yielded the ra-
cemic alcohol products in moderate to good yields, using
an excess of the primary alcohol.[14] In addition, Yus and
co-workers demonstrated that either alkylated ketones or
the corresponding racemic secondary alcohols could be ob-
tained, depending on the stoichiometry between the reac-
tants in the presence of a ruthenium–DMSO complex.[15]
Furthermore, the transformation has been described with
catalysts based on Rh, Pd, and Fe,[16] and, recently, even
under catalyst-free conditions.[17]
To the best of our knowledge, there is only one com-
munication that describes the asymmetric reductive α-alkyl-
ation transformation of acetophenones into enantiomer-
ically enriched alcohols with an elongation of the alkyl
chain (Scheme 2).[18] However, this method, reported by
Uemura and co-workers, is an example of a sequential reac-
tion, which requires the use of two different catalysts to
carry out the transformation.
During the last decade, we have investigated a series of
Ru and Rh complexes containing different chiral ligands
based on amino acids, and employed these as catalysts for
the asymmetric transfer hydrogenation (ATH) of aryl
ketones in 2-propanol.[19] For the most efficient ruthenium
half-sandwich catalyst, the scope was successfully expanded
to allow for ethanol as hydrogen donor for the asymmetric
reduction of substituted acetophenones.[20] However, in this
ethanol ATH protocol, the appearance of a small amount
of a byproduct was observed along with the desired second-
ary alcohol. Analyzing the nature of this impurity, we found
that it consisted of a different enantiomerically enriched
alcohol, resulting from the full reduction of the condensa-
tion product of the corresponding acetophenone with acet-
Scheme 1. α-Alkylation of methyl aryl ketones with primary
alcohols.
[a] Department of Organic Chemistry, The Arrhenius Laboratory,
Stockholm University,
10691 Stockholm, Sweden
E-mail: hans.adolfsson@su.se
www.organ.su.se
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403032.
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O. O. Kovalenko, H. Lundberg, D. Hübner, H. Adolfsson
SHORT COMMUNICATION
Scheme 2. One-pot sequential reactions of acetophenones with alcohols in the presence of an achiral iridium catalyst, followed by a chiral
ruthenium complex, developed by Uemura and co-workers.[18]
Scheme 3. Tandem α-alkylation/ATH reaction of acetophenone with primary alcohols.
aldehyde, which forms in situ when the hydride donor eth- An evaluation of the optimal concentration was performed
anol is oxidized by the metal catalyst. This was intriguing, by changing the amount of DMSO while keeping the quan-
not only in view of the asymmetric tandem process, which tity of EtOH constant at 3 equiv. relative to acetophenone.
appeared to have occurred, but also since acetaldehyde can It was found that the best yield of 1-phenyl-1-butanol was
be a troublesome coupling partner in regular aldol chemis- obtained at a concentration of 2 m, which corresponds to
try, because of self-condensation. In the current communi- an approximate molar ratio of 4:3 for DMSO/EtOH. This
cation, we present the optimized catalytic protocol, which – molar ratio of DMSO to primary alcohol was further em-
to the best of our knowledge – is the first example of the ployed in the reactions using nPrOH and nBuOH as hydride
direct formation of enantiomerically enriched secondary source and coupling agent. We have previously reported
alcohols from ketones and primary alcohols by a tandem that the addition of LiCl has a positive effect on the cata-
α-alkylation/asymmetric transfer hydrogenation process lytic activity and the enantioselectivity in ATH of ketones
with one single catalyst (Scheme 3).
with this class of ruthenium catalysts.[21] The same benefi-
ciary effect was obtained also in the tandem α-alkylation/
ATH process when 10 mol-% of LiCl was used as an addi-
tive.
Results and Discussion
Starting from the conditions used in our previous
work,[20] amino acid hydroxyamide ligand I and [Ru-
(p-cymene)Cl2]2 were applied in catalytic amounts in the
optimization of the tandem process, with acetophenone as
model substrate and ethanol as hydrogen donor and source
of the condensing aldehyde. Different bases were evaluated,
and KOtBu was found to be the most proficient with a
loading of 50 mol-%; these conditions were maintained for
all further reactions in the study. We had previously found
that the reaction rate increased when THF was used as co-
solvent for the asymmetric transfer hydrogenation of aceto-
phenones, using catalytic amounts of [Ru(p-cymene)Cl2]2 in
Scheme 4. Schematic reaction mechanism for the tandem α-alkyl-
ation/ATH reaction.
As expected, increasing the temperature and reaction
combination with ligand I.[21] In contrast, DMSO was time led to higher conversion of the product alcohol, but
found to decrease the rate for the acetophenone reduction, unfortunately also resulted in a decrease in enantio-
and it was therefore chosen as solvent for the tandem α- selectivity.[19h] Optimization of the procedure with respect
alkylation/ATH reaction.[21,22] A schematic reaction mecha- to chemoselectivity and enantioselectivity led to the follow-
nism for the process is depicted in Scheme 4, indicating that ing conditions: the reaction mixture was kept at 65 °C for
the reaction requires a minimum of 2 equiv. of alcohol to 30 min, thereafter the temperature in the oil bath was de-
reach full conversion. In practice, we found that the best creased to 40 °C, and the solution was stirred for an ad-
result was obtained by using 3 equiv. of ethanol, conducting ditional 4.5 hours. By this procedure, 1-phenyl-1-butanol
the experiments in 1 m solutions in a DMSO/EtOH mixture. was isolated in 42% yield with 86% ee.[23]
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Tandem α-Alkylation/Asymmetric Transfer Hydrogenation
Acetophenones containing either electron-rich or elec-
tron-poor substituents were evaluated under the optimized
conditions. The results in Table 1 show that electron-donat-
ing groups in the phenyl ring of acetophenone promote bet-
ter yields, whereas electron-deficient rings give rise to lower
yields (Table 1, entries 1–3 vs. 4–5). These results are in ac-
cordance with what is expected for enolate condensation
reactions. The ee of the products was found to follow the
same trend, being higher for substrates with electron-rich
aryl substituents.
Conclusions
We have demonstrated that the in situ generated catalyst
based on [Ru(p-cymene)Cl2]2 and amino acid hydroxyamide
ligand I mediates the tandem α-alkylation/asymmetric
transfer hydrogenation process. A series of differently sub-
stituted acetophenones were successfully alkylated with
simple primary alcohols, which served as both alkylating
and reducing agents. The resulting secondary alcohols were
isolated in moderate yields with enantioselectivities up to
89%.
Table 1. Tandem α-alkylation/ATH of acetophenones with primary
alcohols.[a]
Experimental Section
General Procedure for the Catalytic Tandem α-Alkylation/Asymmet-
ric Transfer Hydrogenation Reaction: To a 20 mL vial equipped
with a septum and stirring bar, were added [Ru(p-cymene)Cl2]2
(0.0153 g, 0.025 mmol), ligand I (0.0135 g, 0.055 mmol), and LiCl
(0.0212 g, 0.500 mmol). The atmosphere in the vial was exchanged
by means of three consecutive vacuum/Ar cycles. Dry DMSO
(1.6 mL), ROH (R = Et, nPr, nBu; 15.0 mmol), and substrate
(5.0 mmol) were added. The mixture was allowed to stir for 10 min,
thereafter KOtBu (0.280 g, 2.5 mmol) was added. The vial was sub-
sequently sealed and placed in an oil bath at 65 °C with vigorous
stirring for 30 min. Thereafter, the temperature in the bath was de-
creased to 40 °C, and the stirring was continued for additional
4.5 h. Brine (20 mL) was added, and the mixture was extracted with
EtOAc (4ϫ20 mL). The combined organic layers were dried with
Na2SO4 and concentrated under reduced pressure. The resulting
oily residue was purified by column chromatography (for details,
see Supporting Information).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and compound characterizations.
Acknowledgments
[a] For the reaction conditions, see the Experimental Section. [b]
Isolated yields. [c] Determined by HLPC (CHIRALCEL OB or
CHIRALCEL OJ). [d] Determined by GLC (CP Chirasil DEX
CB).
The K & A Wallenberg Foundation and the Swedish Research
Council are greatly acknowledged for financial support. We would
like to thank Drs. E. Buitrago, P. Ryberg, and H. G. Andersson for
fruitful discussions at the early stage of this project.
All obtained alcohols have positive optical rotation val-
ues when the R,R-diastereomer of ligand I was used. Com-
parisons with literature data confirmed that this corre-
sponds to the R-isomers for 1-phenyl-1-butanol, 1-phenyl-
1-pentanol, and 1-phenyl-1-hexanol.[24]
Performing the tandem α-alkylation/ATH reaction be-
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Received: August 4, 2014
Published Online: September 15, 2014
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Eur. J. Org. Chem. 2014, 6639–6642