Chemoselective formation of unsymmetrically substituted ethers from catalytic reductive coupling of aldehydes and ketones with alcohols in aqueous solution

Article abstract of DOI:10.1021/acs.orglett.5b00553

A well-defined cationic Ru-H complex catalyzes reductive etherification of aldehydes and ketones with alcohols. The catalytic method employs environmentally benign water as the solvent and cheaply available molecular hydrogen as the reducing agent to afford unsymmetrical ethers in a highly chemoselective manner.

Full text of DOI:10.1021/acs.orglett.5b00553

Letter
pubs.acs.org/OrgLett
Chemoselective Formation of Unsymmetrically Substituted Ethers
from Catalytic Reductive Coupling of Aldehydes and Ketones with
Alcohols in Aqueous Solution
Nishantha Kalutharage and Chae S. Yi*
Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881 United States
S
* Supporting Information
ABSTRACT: A well-defined cationic Ru−H complex cata-
lyzes reductive etherification of aldehydes and ketones with
alcohols. The catalytic method employs environmentally
benign water as the solvent and cheaply available molecular
hydrogen as the reducing agent to afford unsymmetrical ethers
in a highly chemoselective manner.
therification of oxygenated organic compounds is an
unsymmetrical ethers. In an effort to extend the scope of the
Eubiquitous organic transformation in both industrial and etherification reaction, we explored the analogous reductive
fine chemical syntheses.1 Strong Brønsted acid and heteroge-
coupling reactions of carbonyl compounds. Herein, we report a
highly chemoselective formation of unsymmetrically substituted
ether products from the reductive coupling of aldehydes and
ketones with alcohols. The “green” features of the catalytic
method are that it employs cheaply available molecular hydrogen
as the reducing agent, tolerates a number of common functional
groups, and uses environmentally benign water as the solvent.
We initially screened the catalyst activity of the ruthenium
complex 1 for the reductive coupling reaction of 2-butanol with
4-methoxybenzaldehyde (eq 1). While searching for a suitable set
neous acid catalysts are commonly employed for industrial-scale
etherification of alcohols,2 while the Williamson ether synthesis
has long been used for laboratory-scale synthesis of unsym-
metrically substituted ethers.3 Seminal catalytic C−O bond
formation methods such as Ullmann- and Mitsunobu-type
coupling reactions have been extensively utilized for the synthesis
of aryl-substituted ethers.4 More recently, a number of highly
effective catalytic methods for unsymmetrical ethers have been
developed from use of hydroalkoxylation of alkenes5 and
oxidative C−H alkoxylation of arenes.6 The reductive ether-
ification of carbonyl compounds has also been shown to be a
synthetically powerful etherification method, but this method
requires a stoichiometric amount of silane as the reducing agent.7
Despite such remarkable progress, these catalytic etherification
methods pose major synthetic and environmental problems in
that they employ reactive reagents such as inorganic acids and
organic alkoxide substrates, which result in the formation of
copious amounts of wasteful byproducts. From the viewpoint of
achieving green and sustainable catalysis, the development of an
efficient and broadly applicable catalytic etherification process
that does not form any wasteful byproducts remains a high
priority goal, particularly for the synthesis of unsymmetrically
substituted ethers.8
of conditions, we were delighted to discover that H2 (1−2 atm)
can be used as the reducing agent and water as the solvent. Under
these conditions, complex 1 was found to exhibit distinctively
high activity and selectivity in forming the ether product 2a
among screened ruthenium and acid catalysts, as analyzed by
both GC and NMR spectroscopic methods (Table S1,
Supporting Information (SI)). Since most reductive ether-
ifications of carbonyl compounds require a stoichiometric
amount of silane or borane as the reducing agent,7 our catalytic
We recently discovered that a well-defined cationic ruthenium
hydride complex [(C6H6)(PCy3)(CO)RuH]+BF4 (1) is a
−
highly selective catalyst precursor for the etherification of two
different alcohols to form unsymmetrically substituted ethers.9
While this etherification provides unsymmetrical ethers without
forming any wasteful byproducts, it was not effective for the
coupling between electronically similar or sterically demanding
aliphatic alcohols, as it gave a mixture of symmetrical and
Received: February 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00553
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Organic Letters
Letter
method on using molecular H2 is quite beneficial from both
synthetic and environmental points of view.
was observed in yielding the ether product 2i (entry 9). The
coupling between aliphatic alcohol and aldehyde substrates was
sluggish, leading to a lower yield than with benzylic ones (entries
12 and 13). In this case, extending the reaction time to 24 h did
not increase the product yield significantly.
We measured the catalytic activity of 1 for the etherification
reaction. In a Fisher−Porter pressure bottle, the treatment of 4-
methoxybenzaldehyde (20 mmol) with 2-butanol (23 mmol)
and H2 (20 psi) in the presence of 1 (1.7 × 10−3 μmol) in water
(3 mL) was stirred at 110 °C. The initial turnover frequency
(TOF) of 5100 h−1 after 30 min and the turnover number
(TON) of 25500 after 18 h were obtained as measured by both
GC and NMR spectroscopic methods. The etherification
reaction under neat conditions led to a considerably higher
activity for 2a (TOF = 7600 h−1 and TON = 32000). The salient
feature of the catalytic method is that it employs cheaply available
H2 as the reducing agent in an aqueous solution.
Substrate scope of the etherification reaction was explored by
using the catalyst 1 (Table 1). Both aliphatic and aryl-substituted
aldehydes readily reacted with both primary and secondary
alcohols to form the ether products 2 (entries 1−13). In the case
of 1,2-hexanediol, exclusive etherification to the primary alcohol
The etherification of ketones also proceeded smoothly to give
the α-substituted ether products. The aryl-substituted ketones
with both primary and secondary alcohols led to the
corresponding ether products 2n−x (entries 14−24). The
coupling with a linear aliphatic ketone was found to be
considerably slower than with benzylic ketones (entry 25).
The treatment of a chiral alcohol with 4-methoxyacetophenone
led to a 1:1 diastereomeric mixture of ether product 2z (entry
26). In most cases, using 2 equiv of alcohol substrate (second
equivalent alcohol is served as the hydrogen donor) was found to
be convenient for forming the ether products, but 1 equiv of
alcohol substrate can be used with H2 (1−2 atm) without
sacrificing the product yields. In addition, a 1:1 toluene/H2O was
used as the solvent system in most cases, and pure water was used
for water-soluble substrates. The catalytic method achieves a
highly chemoselective etherification of aldehydes and ketones
without using any reactive reagents, and employs environ-
mentally sustainable and cheaply available alcohol substrates.
To further illustrate the synthetic versatility of the catalytic
method, we next surveyed the etherification reaction of
functionalized alcohol substrates of biological importance
(Figure 1). The etherification of (−)-menthol and 2′,3′-
Table 1. Etherification of Alcohols with Aldehydes and
a
Ketones
Figure 1. Etherification biologically active alcohols with aldehydes.
Reaction conditions: alcohol (1.0 mmol), aldehyde (1.0 mmol), H2 (1
atm), C6H5Cl (2 mL), 1 (3 mol %), 110 °C.
isopropylidenedeoxyuridine with 4-methoxybenzaldehyde
smoothly formed the ether product 3a and 3b without any
epimerization or side products. The etherification reaction of an
amino acid and steroid derivatives with 4-methoxybenzaldehyde
also proceeded predictively to give the products 3c−e, while
displaying high chemoselectivity toward the ether product
formation. An aliphatic aldehyde was successfully used for
fenofibrate and chloroamphenicol, where in the latter case, a
selective etherification to the primary alcohol was achieved over
the secondary one in forming the ether product 3h. In these
cases, a nonprotic solvent chlorobenzene was found to be most
suitable for the coupling reaction, as the substrates become
insoluble in toluene/H2O solvent. The structure of 3e was
determined by X-ray crystallography (Figure S6, SI).
a
Reaction conditions: carbonyl compound (1.0 mmol), alcohol (2.0
mmol), toluene/H2O (v/v = 1:1, 3 mL), 1 (3 mol %), 110 °C.
b
Reaction in pure water (3 mL).
B
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A series of kinetic experiments were performed to gain
mechanistic insights for the etherification reaction. First, the H/
D exchange pattern on the coupling reaction was examined. The
treatment of 4-methoxybenzaldehyde with 1-butanol (2 equiv)
in D2O led to the selective deuterium incorporation to benzylic
position of the product 2f (Scheme 1). Conversely, 4-
Scheme 1
Figure 3. Hammett plot from the reaction of p-XC6H4CHO (X = OMe,
Me, H, F, Cl) with 2-butanol.
To discern the structure of catalytically relevant species, we
explored the reactions of 1 with alcohols and water. The
treatment of the complex 1 (0.07 mmol) with excess 1-butanol
(0.7 mmol) in CD2Cl2 (0.6 mL) led to the formation of a new
Ru−H species within 30 min at room temperature (Scheme 2).
methoxybenzaldehyde with 2-propanol-d8 (2 equiv) in H2O
gave the product with ∼50% of deuterium on the benzylic
position. In a control experiment, the treatment of 2-propanol
with D2O in the presence of 1 (2 mol %) led to a rapid H/D
exchange to form (CH3)2CHOD at room temperature. These
results suggest that an extensive H/D exchange between the
solvent molecules and the alcohol substrate led to the deuterium
incorporation to the benzylic position of the ether product
during the CO hydrogenolysis step.
Scheme 2
To probe the involvement of solvent molecules, the solvent
isotope effect was measured on the catalytic reaction. The initial
rates of the reaction between 4-methoxybenzaldehyde with 2-
butanol (2 equiv) were separately measured in H2O and D2O.
The first order plots showed a relatively high normal isotope
effect of kH2O/kD2O = 2.9 0.2 (Figure 2). A similar solvent
The appearance of a new set of peaks was observed along with the
formation of free benzene molecule as monitored by NMR (1H
NMR: δ −18.8 (d, JPH = 31.3 Hz) ppm; 31P{1H} NMR: δ 76.0
ppm). We tentatively assign the new species to the alcohol-
coordinated complex [(1-butanol)3(PCy3)(CO)RuH]+BF4
−
(4a), in light of the previously observed arene exchange reaction
of 1.12 The analogous reaction with excess water also formed the
water-coordinated complex 4b (1H NMR: δ −17.7 (d, JPH = 30.3
Hz) ppm; 31P{1H} NMR: δ 73.0 ppm), which steadily
decomposed within 1 h at room temperature. The catalytic
activity of complex 4a was found to be identical to 1 for the
etherification of 4-methoxybenzaldehyde with 2-butanol under
the conditions described in eq 1.
We next examined the reaction of complex 1 with diols and
triols as a way to form a stable alcohol-coordinated complex.
Thus, the treatment of 1 with 1,1,1-tris(hydroxymethyl)ethane
in acetone at room temperature led to the triol-coordinated
complex 4c, which was isolated in 80% after recrystallization in
acetone/pentane. The X-ray crystal structure of 4c showed a
distorted octahedral geometry with a facial arrangement between
the triol and the ancillary ligands. A number of ruthenium−
hydride complexes have been successfully utilized as catalysts for
the alcohol-coupling reactions.13
We present a possible mechanism of the catalytic reaction on
the basis of these results (Scheme 3). We propose that an
unsaturated cationic Ru−alkoxy (or Ru−alcohol) species 5 is
initially generated from the benzene ligand displacement and the
dehydrogenation steps. In support of this notion, we have been
able to detect/isolate the formation of alcohol-coordinated
cationic Ru−H complex 4 from the reaction of 1 with alcohols
and water. The coordination of a carbonyl substrate followed by
the nucleophilic addition of an alkoxy group is envisioned for the
Figure 2. First-order plot of the 4-methoxybenzaldehyde (S) with 2-
butanol in H2O ( ) and in D2O ( ).
▲
●
isotope effect was obtained from 2-propanol/2-propanol-d8
(kPrOH/kPrOD = 2.0
0.2, Figure S3, SI). A relatively large
solvent isotope effect suggests that the water molecules are
intricately involved in C−O bond cleavage and hydrogenolysis
steps via extensive hydrogen-bonding-network interactions.10
To probe the electronic effect on the aldehyde substrate, we
constructed a Hammett plot from measuring the rate of a series
of para-substituted benzaldehydes p-X-C6H4CHO (X = OMe,
Me, H, F, Cl) with 2-butanol. A linear correlation from the
relative rate vs Hammett σp led to a negative ρ value of −1.6 0.1
(Figure 3). The result is consistent with the notion that an
electron-releasing group promotes the C−O bond hydro-
genolysis step but not during the formation of hemiacetal
species. Similar Hammett ρ values have been observed in the
catalytic coupling reactions of arenes.11
C
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Scheme 3. Possible Mechanism for the Reductive
Etherification of an Alcohol with an Aldehyde
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selective catalytic etherification method of aldehydes and ketones
with alcohols. The ruthenium hydride catalyst exhibits a uniquely
high activity as well as broad substrate scope in promoting the
reductive etherification reaction of carbonyl compounds in an
aqueous solution without using any reactive reagents or forming
wasteful byproducts. We anticipate that the catalytic ether-
ification method provides an environmentally sustainable and
cost-effective protocol for forming unsymmetrical ether
compounds.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and methods, characterization and
NMR spectra, and X-ray data of 3e and 4c (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
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(b) Fedorov, A.; Chen, P. Organometallics 2010, 29, 2994−3000.
(c) Chakraborty, S.; Blacque, O.; Fox, T.; Berke, H. ACS Catal. 2013, 3,
2208−2217. (d) Ball, L. T.; Lloyd-Jones, G. C.; Russell, C. A. J. Am.
Chem. Soc. 2014, 136, 254−264.
AUTHOR INFORMATION
Corresponding Author
■
(12) (a) Kwon, K.-H.; Lee, D. W.; Yi, C. S. Organometallics 2010, 29,
5748−5760. (b) Lee, H.; Yi, C. S. Eur. J. Org. Chem. 2015, 1899−1904.
*E-mail: chae.yi@marquette.edu.
Notes
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̈
(b) Denichoux, A.; Fukuyama, T.; Doi, T.; Horiguchi, J.; Ryu, I. Org.
Lett. 2010, 12, 1−3. (c) Fogler, E.; Balaraman, E.; Ben-David, Y.; Leitus,
G.; Shimon, L. J. W.; Milstein, D. Organometallics 2011, 30, 3826−3833.
(d) Kang, B.; Fu, Z.; Hong, S. H. J. Am. Chem. Soc. 2013, 135, 11704−
11707. (e) Tseng, K.-N. T.; Kampf, J. W.; Szymczak, N. K.
Organometallics 2013, 32, 2046−2049. (f) Pingen, D.; Lutz, M.; Vogt,
D. Organometallics 2014, 33, 1623−1629.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science of Foundation
(CHE-1358439) and National Institute of Health General
Medical Sciences (R15 GM109273) is gratefully acknowledged.
We thank Dr. Sergey Lindeman (Marquette University) for the
X-ray crystal structure determination of 3e and 4c.
(14) In light of the recent results as described in ref 9, we have
considered an alternative mechanism involving the hydrogenation of
carbonyl substrate to the corresponding alcohol and the subsequent
dehydrative coupling with the second alcohol substrate. Since both
mechanistic pathways should involve an alcohol−ketone hydro-
genation−dehydrogenation redox process and a C−O bond hydro-
genolysis step, we cannot distinguish between these two pathways at the
present time.
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