Reductive Etherification via Anion-Binding Catalysis

Article abstract of DOI:10.1021/jacs.7b05832

Reductive condensations of alcohols with aldehydes/ketones to generate ethers are catalyzed by a readily accessible thiourea organocatalyst that operates in combination with HCl. 1,1,3,3-tetramethyldisiloxane serves as a convenient reducing reagent. This strategy is applicable to challenging substrate combinations and exhibits functional group tolerance. Competing reductive homocoupling of the carbonyl component is suppressed.

Full text of DOI:10.1021/jacs.7b05832

Communication
pubs.acs.org/JACS
Reductive Etherification via Anion-Binding Catalysis
Chenfei Zhao, Christopher A. Sojdak, Wazo Myint, and Daniel Seidel*,†
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United
States
S
* Supporting Information
Table 1. Evaluation of Reaction Conditions
ABSTRACT: Reductive condensations of alcohols with
aldehydes/ketones to generate ethers are catalyzed by a
readily accessible thiourea organocatalyst that operates in
combination with HCl. 1,1,3,3-tetramethyldisiloxane
serves as a convenient reducing reagent. This strategy is
applicable to challenging substrate combinations and
exhibits functional group tolerance. Competing reductive
homocoupling of the carbonyl component is suppressed.
eductive aminations are among the most reliable reactions
for amine synthesis due to starting material availability, mild
R
reaction conditions, and broad substrate scope (Figure 1).1 In
contrast, the corresponding reductive etherifications are less
developed.2 This is despite the availability of the prerequisite
starting materials and the advantages such an approach would
offer over classical methods such as the Williamson ether
synthesis.3 Significant efforts have been dedicated toward
development of a general method for reductive etherification.
Known strategies are based on transition metal catalysts,4 Lewis
acids,5 and Brønsted acids.6 Methods relying on silylated alcohols
rather than unprotected alcohols have also emerged.7−9 Despite
these advances, a number of challenges have yet to be addressed
to allow for a broader application of this process. Remaining
limitations include first and foremost functional group
compatibility, but also suppression of reductive homocoupling
of the aldehyde or ketone component,10 and applicability to
challenging substrates such as aromatic ketones. Here we report a
new concept for reductive etherification that is based on the
a
entry
catalyst
acid
silane
Et3SiH
time [h]
yield (%)
1
TFA
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
24
24
24
24
24
24
24
24
24
24
24
5
6
2
Et3SiH
44
3
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1a
Et3SiH
64
4
Et3SiH
74
5
PhSiH3
Ph2SiH2
Me2PhSiH
PMHS
21
6
34
7
95
8
12
9
Ph3SiH
MePhSiH2
(EtO)2MeSiH
TMDS
46
10
11
12
13
14
15
66
trace
98
TMDS
20 min
24
24
1
98 (94)
92
TMDS
TMDS
70
b
16
c
1c
1c
TMDS
97
17
TMDS
24
91
a
NMR yields (1,3,5-trimethoxybenzene as internal standard), number
in parentheses corresponds to isolated yield; HCl was used as 4.2 M
b
c
solution in dioxane. With 2 mol % of thiourea. With 0.3 equiv of
HCl.
cooperative action of a readily accessible organocatalyst, HCl,
and a simple silane reductant.
Mirroring the requirements for reductive amination, a method
for reductive etherification needs to facilitate condensation of an
aldehyde/ketone with an alcohol to generate an oxocarbenium
ion or related intermediate. The latter has to be reduced
selectively over the aldehyde/ketone starting material. We
envisioned the cooperative use of a simple Brønsted acid and a
thiourea catalyst in the presence of an appropriate reducing agent
Received: June 6, 2017
Figure 1. Reductive amination vs etherification and new concept.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b05832
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Optimization of Conditions for an Aliphatic
Aldehyde
Scheme 1. Substrate Scope
a
entry
silane
time
yield of 2b (%)
2b:3
1
2
3
4
5
6
TMDS
20 min
3 h
76
8:1
Et3SiH
81
14:1
9:1
PhSiH3
24 h
59
Ph3SiH
24 h
66
14:1
15:1
25:1
Me2PhSiH
MePhSiH2
30 min
2 h
78
92 (87)
a
NMR yields (1,3,5-trimethoxybenzene as internal standard), number
in parentheses corresponds to isolated yield.
might allow for an efficient reductive etherification process
(Figure 1).11,12 Specifically, the thiourea catalyst is expected to
facilitate the Brønsted acid promoted formation of the
oxocarbenium ion intermediate and/or increase its equilibrium
concentration. Interaction of the counteranion of the oxocarbe-
nium cation with the thiourea catalyst via anion-binding should
serve to increase the electrophilicity of the oxocarbenium
cation.13,14 In addition, the sulfur atom of the thiourea moiety
may potentially serve as a Lewis base capable of interacting with
the reducing reagent.14r,15 The concept of anion-binding catalysis
was first proposed by Schreiner and co-workers,16 and is
recognized as a general activation mode.13
Para-tolualdehyde and benzyl alcohol were selected as model
substrates to evaluate the proposed reductive etherification
reaction (Table 1). In the absence of a thiourea catalyst with TFA
as the Brønsted acid promoter and Et3SiH as the reducing
reagent, only trace amounts of product 2a were observed after 24
h and starting materials remained mostly unaffected (entry 1).
The use of HCl in an otherwise identical experiment provided 2a
with markedly increased yield (entry 2). As a proof of concept,
addition of the well-known Schreiner thiourea catalyst (1a)17 at a
5 mol % loading resulted in a further increase in yield (entry 3).
Modified Schreiner catalyst 1b, bearing bromine substituents
between the trifluoromethyl groups, enabled further acceleration
of the reductive etherification (entry 4). A number of different
silanes were evaluated with catalyst 1b (entries 5−12). Among
the reducing reagents, 1,1,3,3-tetramethyldisiloxane (TMDS)18
stood out as highly efficient. Although none of the reactions in
entries 1−11 went to completion within 24 h, the corresponding
reaction with TMDS led to complete consumption of aldehyde
within 5 h and provided 2a in excellent yield (entry 12). We
rationalized further improvements in efficiency may be achieved
by replacing the bromo substituents in 1b for more electron-
withdrawing cyano groups. The corresponding thiourea catalyst
1c reduced the required reaction time to 20 min with no loss in
efficiency (entry 13). The difference to catalyst 1a is profound:
under otherwise identical conditions, trace amounts of starting
material were present after 24 h (entry 14). In the absence of any
thiourea catalyst, the reaction slowed (entry 15). Use of catalyst
1c at a loading of 2 mol % was equally efficient with regard to
product yield but required a slightly prolonged reaction time
(entry 16). However, a decrease in the amount of HCl led to a
significant slowdown of the reaction (entry 17).19
a
b
c
MePhSiH2 was used instead of TMDS; With 1.2 equiv of HCl; 1b
d
was used instead of 1c; With 2.4 equiv of p-tolualdehyde, 10 mol % of
1c, 1.2 equiv of HCl, and 2.4 equiv of TMDS.
Scheme 2. Scale-Up Reaction at Lower Catalyst Loading
Under the optimized conditions of Table 1, reductive
homocoupling of p-tolualdehyde was not observed. However,
this undesired side reaction is known to occur in certain Brønsted
acid catalyzed reductive etherification reactions.6a,c The com-
peting reaction pathway not only compromises reaction yields
but also complicates product purification. As we were exploring
the substrate scope, such homocoupling side products were
observed with aliphatic aldehydes, presumably due to an
B
DOI: 10.1021/jacs.7b05832
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
case. In the formation of product 2w, analysis of the crude
reaction mixture indicated a 6.8:1 ratio of 2w and reductive
homocoupling product.20
To further demonstrate the practicality of the process, the
reductive etherification of p-tolualdehyde and L-menthol was
performed on a 10 mmol scale with 1 mol % of 1c (Scheme 2).
The reaction went to completion within 1 h and provided
product 4 in 95% yield. In the absence of 1c under otherwise
identical conditions and reaction scale, the reaction remained
incomplete after 24 h (66% conversion).
Table 3. Binding Constants (Ka) of the Catalysts with TBACl
catalyst
Ka (M−1
)
b
1a
1b
1c
39.1 0.49 (41)
41.7 0.46
81 2.2
The dramatic differences in catalytic activity of the different
thioureas are striking. In an attempt to correlate the reactivity
differences of the catalysts with their chloride affinities, binding
constants for chloride were determined via NMR titrations of the
thiourea catalysts with tetrabutylammonium chloride in
deuterated DMSO containing 0.5% water (Table 3, Figure
2).21,22 Though perhaps not fully accounting for the substantially
greater activity of 1c, this catalyst showed a 2-fold binding affinity
for chloride compared to 1a and 1b.
a
Thiourea catalyst (0.01 M) in DMSO-d6/0.5% H2O was titrated with
b
tetrabutylammonium chloride (TBACl); Ka value in parentheses is
from ref 21.
In summary, we have developed a method for direct reductive
etherification where a readily accessible thiourea organocatalyst
is used in combination with a simple Brønsted acid. Challenging
substrates such as aromatic ketones and various functional
groups were well tolerated.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b05832.
Figure 2. Titrations of thioureas (0.01 M) with TBACl in DMSO-d6/
0.5% H2O. The chemical shifts refer to the thiourea N−H protons.
Binding constant studies, synthesis of catalysts, and
preparation and characterization data of products (PDF)
increased propensity of these substrates to undergo reduction.
For instance, the reaction of cyclohexanecarboxaldehyde and
benzyl alcohol provided an 8:1 mixture of desired product 2b and
undesired homocoupling product 3 (Table 2, entry 1). We
speculated the product distribution may be shifted toward the
desired product by utilizing a silane with attenuated reactivity.
Upon evaluation of a number of silanes summarized in Table 2,
methylphenylsilane was optimal in favoring product 2b (Table 2,
entry 6).
The scope of the reductive etherification is shown in Scheme 1.
With regard to aromatic aldehydes, different substitution
patterns and electronic properties were well tolerated. Linear,
α-branched, and nonenolizable aliphatic aldehydes also
performed well with methylphenylsilane as the reductant.
Furthermore, cyclic and acyclic aliphatic ketones were viable
substrates. Notably, in contrast to previous reports using
Brønsted and Lewis acids, aromatic ketones demonstrated
good reactivity. To our knowledge, the only direct reductive
etherification method where aromatic ketones provide satisfac-
tory yields calls for a ruthenium-hydride complex that requires
handling in a glovebox.4e Various alcohols participated in
reductive etherification. Ethylene glycol efficiently underwent
double etherification. Importantly, the reaction was compatible
with a range of functionalities including ether, alkyl and aryl
halide, nitro, ester, nitrile, thienyl, amide, carbamate, alkenyl, and
alkynyl groups. While the standard reaction conditions were
seemingly incompatible with the presence of an imide due to
partial reduction of this functional group, replacement of catalyst
1c for 1b allowed for the isolation of imide-containing product
2aa in good yield. Notably, only trace amounts, if any, of
reductive homocoupling products were observed in all but one
AUTHOR INFORMATION
■
Corresponding Author
*seidel@chem.ufl.edu
ORCID
Christopher A. Sojdak: 0000-0002-1176-6736
Daniel Seidel: 0000-0001-6725-111X
Present Address
†Department of Chemistry, University of Florida, Gainesville,
Florida 32611, United States.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This material is based upon work supported by the National
Science Foundation under Grant No. CHE-1300382.
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D
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