.
Angewandte
Communications
[
12]
taining a tripodal phosphine ligand. Later on, significant
improvements regarding efficiency and functional-group
The direct synthesis of ethers by intermolecular reductive
coupling of carboxylic acids and alcohols using H as the
2
[
13]
tolerance of ester reduction have been achieved. In 2006,
a general catalytic hydrogenation of esters was developed by
Milstein and co-workers by using a defined Ru/PNN-type
reductant is a neglected challenge, although it constitutes an
ideal alternative to the known reductive etherifications from
[
23]
ketones or aldehydes. To the best of our knowledge such
reactions have not been reported yet. Gratifyingly, efficient
conversion of carboxylic acids and primary alcohols into the
corresponding esters was achieved under similar reaction
conditions using toluene as the solvent. In all cases, the
desired reductive coupling reactions proceeded well with full
conversion and good yields of the expected products
(Scheme 2, 46–84%). Aliphatic acids are more difficult
[
14]
pincer ligand complex. In addition, Saudan and co-workers
demonstrated that a Ru/bis(aminophosphine) complex allows
efficient hydrogenation of a broad range of esters in the
[
15]
presence of alkali base additives.
ruthenium catalysts with pincer ligands were used in this
More recently, new
[16]
[17]
area by researchers in Takasago and the group of Gusev.
In continuation of our previous efforts towards ester reduc-
tion, our idea of converting esters into ethers was initially
inspired by the successful application of Lewis acids for
[
18]
cleavage of CꢀO bonds to promote reactions such as S 1-type
N
amination of alcohols, oxygenolysis of alcohols, and tertiary
[19]
ethers to alkenes etc.
Though oxophilic aluminum salts
constitute an easy-to-envisage choice for selective cleavage of
the CꢀOH bond during hydrogenations of esters to ethers,
unfortunately all ester hydrogenation systems mentioned
above have not been shown to be compatible with Lewis
acids. Herein, we report the first catalytic deoxygenative
hydrogenation of esters to the corresponding ethers by the
combined use of a specific ruthenium-phosphine catalyst and
Lewis acids such as Al(OTf) or Hf(OTf) .
Scheme 2. Direct reductive coupling of carboxylic acids with primary
alcohols. Reaction conditions: 0.5 mmol carboxylic acid, 10 mmol
1
alcohol. Yields were determined by GC and H NMR spectroscopy
using n-hexadecane and anisole, respectively, as the internal standard.
[a] 2 mL toluene as the solvent. [b] 10 mL toluene as the solvent.
3
4
Based on our recent work on reductive amination of
[
20]
carbon dioxide,
we performed the hydrogenation of
substrates compared to the aromatic ones and longer reaction
times are required to get moderate yields. Lower yields
(< 20%) of ether products were obtained when secondary
alcohols were used, probably because of the difficulty of
etherification step and/or the instability of the products in the
presence of water.
levulinic acid (1a) in the presence of [Ru(acac) ] (acac =
acetylacetonate), CH C(CH PPh ) (triphos), and lithium
3
3
2
2 3
halides. However, after extensive screening no desired
reaction took place and in all the cases the hydrogenation
reactivity was totally suppressed (see Table S1 in the Sup-
porting Information). Meanwhile, aluminium-based Lewis
acids, which have been proven to control heterogeneous
hydrogenations of phenol to cyclohexanone through specific
Al-O interactions, were tested. To our delight, Al(OTf)3
was found as an active cocatalyst and improved the efficiency
of the benchmark 2-MeTHF synthesis reaction from levulinic
acid following sequential ketone reduction/intramolecular
condensation/deoxygenative
Eq. (1); acac = acetylacetonate, THF = tetrahydrofuran].
Compared to the reported method (1608C, 100 atm of H ),
[
21]
Since the etherifications described above should occur via
the corresponding ester intermediates, the general applic-
ability of this methodology was investigated for the synthesis
of ethers through hydrogenation of esters. Various aliphatic
and aromatic lactones, linear esters, and one diester were
hydrogenated in the presence of the dual Ru-Al catalyst
system (Table 1). Notably, high conversions and good yields
(GC) were obtained for all the reactions in Table 1. In
general, the reactivity order was observed to be aliphatic g-
lactones > aliphatic d-lactones > aromatic g-lactones @ linear
esters. In some cases, because of the volatile character of the
products the yields of the isolated compounds were lower
than expected. The reduction of g-lactones and d-lactones
occurred smoothly and gave 2e–o in 46–85% yield. Notably,
the reduction of more sensitive a-hydroxy lactones to
hydroxy tetrahydrofurans proceeded well at 1308C with
moderate to very good yields (2p–r). At higher temperature,
also phthalides and coumaranone can be reduced to the
desired products (2s–u). This novel methodology can also be
employed with more challenging acyclic esters (1v and 1w)
and mediocre yields were obtained with high conversions (30–
[
22]
hydrogenation
reactions
[
2
[
9b]
milder reaction conditions were used.
a 100 mmol scale provided 2-MeTHF (7.6 g) in 88% yield
when using 0.1 mol% of the ruthenium catalyst formed in situ
from [Ru(acac) ] and triphos, without special precautions (use
of commercial reagents in the absence of inert gas).
The reaction on
3
4
6% yield). The main by-products (mainly different alcohols)
were generated from side reactions with THF, and were
After intramolecular etherification of acid and ketone
groups was achieved using the in situ formed Ru/triphos
caused by undesired nucleophiles generated by CꢀO bond
cleavage of THF. It is worth noting that unsymmetrical acyclic
methyl and ethyl ethers can be obtained with much higher
yields by addition of extra methanol or ethanol to the
complex and Al(OTf) , we were interested in investigating
3
the more challenging intermolecular version of this reaction.
2
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!