Ether Synthesis through Reductive Cross-Coupling of Ketones with Alcohols Using Me 2 SiHCl as both Reductant and Lewis Acid

Article abstract of DOI:10.1055/s-0036-1590838

We report that a Lewis acidic silane, Me ₂ SiHCl, can mediate the direct cross-coupling of a wide range of carbonyl compounds with alcohols to form dialkyl ethers. The reaction is operationally simple, tolerates a range of polar functional groups, can be utilized to make sterically hindered ethers, and is extendable to sulfur and nitrogen nucleophiles.

Full text of DOI:10.1055/s-0036-1590838

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
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Y. H. Lee, B. Morandi
Cluster
Synlett
Ether Synthesis through Reductive Cross-Coupling of Ketones
with Alcohols Using Me2SiHCl as both Reductant and Lewis Acid
Reductant & Lewis acid
Yong Ho Lee
Me
Me
Si
Bill Morandi*
H
Si Cl
Me
O
Me
n
Max-Planck-Institut für Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an
der Ruhr, Germany
morandi@kofo.mpg.de
23 examples
up to 82% yield
R1
R2
R2
O
H
Published as part of the Cluster Silicon in
Synthesis and Catalysis
OH
O
R1
O
H
H
MeCN, r.t., 12 h
R3
R4
H
R3
R4
H
64%
HO
Received: 05.05.2017
Accepted after revision: 20.06.2017
Published online: 20.07.2017
conditions.6b,7 In particular, protocols using silanes as re-
ductants benefit from operationally simple procedures and
low toxicity, both of which are attractive features for labo-
ratory-scale synthesis. Unfortunately, besides some excep-
tions,1d,8,9 most of the reports in this area have employed
preformed silyl ethers as substrates, thus limiting the step-
economy and practicality of these reactions.10,11 In 2011,
Roth and co-workers reported the most general solution to
the direct cross-coupling of carbonyls and alcohols using a
silane reductant.9 Using triflic acid as a catalyst and inex-
DOI: 10.1055/s-0036-1590838; Art ID: st-2017-b0329-c
Abstract We report that a Lewis acidic silane, Me2SiHCl, can mediate
the direct cross-coupling of a wide range of carbonyl compounds with
alcohols to form dialkyl ethers. The reaction is operationally simple, tol-
erates a range of polar functional groups, can be utilized to make steri-
cally hindered ethers, and is extendable to sulfur and nitrogen nucleo-
philes.
Key words silanes, Lewis acid, ketones, alcohols, ethers, reductive
coupling
Table 1 Optimization Studiesa
Dialkyl ethers are important compounds in organic syn-
thesis because of their widespread applications in medici-
nal chemistry and their occurrence in many natural prod-
ucts and materials.1 Traditionally, dialkyl ethers have been
formed through the nucleophilic displacement of (pseu-
do)halogens with an alkoxide through the Williamson ether
synthesis.2 However, this procedure has been limited by the
harsh reaction conditions and by the need to convert more
common hydroxyl groups into better leaving groups (e.g.,
Br, OTs) prior to ether bond formation. Moreover, the
Williamson procedure is inherently limited when sterically
congested electrophiles and alkoxides are utilized because
of the formation of side-products through elimination pro-
cesses. While recent creative approaches have addressed
some of the traditional limitations of the Williamson ether
synthesis,3–6 a practical procedure that enables direct ac-
cess to dialkyl ethers, including sterically congested ones,
remains to be developed. In particular, a method that em-
ploys common starting materials and simple reagents
would likely find broad application in synthesis.
Reductant,
Acid or additive
O
+
Solvent, r.t., 12 h
HO
O
(1.1 equiv)
Entry Reductant
(equiv)
Acid or additive
(equiv)
Solvent
GC yield
(%)b
1
2
Et3SiH (1.1)
Et3SiH (1.1)
Et3SiH (1.1)
Et3SiH (1.1)
TfOH (0.03)
MeNO2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeNO2
DCM
22
56
7
TfOH (0.03)
3
Me2SiHCl (0.03)
4
–
–
–
–
–
–
–
–
0
5
Me2SiHCl (1.1)
Ph2SiHCl (1.1)
iPr2SiHCl (1.1)
tBu2SiHCl (1.1)
Me2SiHCl (1.1)
Me2SiHCl (1.1)
Me2SiHCl (1.1)
89 (79)
49
25
3
6
7
8
9
50
52
24
10
11
CHCl3
A straightforward approach to unsymmetrical ether
synthesis proceeds through the reductive cross-coupling of
broadly available carbonyls and alcohols under reducing
a Cyclohexanone (0.25 mmol), solvent (0.5 mL).
b Yields based on GC-FID analysis using dodecane as a standard; yields of iso-
lated products are given in parentheses.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
Y. H. Lee, B. Morandi
Cluster
Synlett
pensive Et3SiH as a reducing agent, they were able to cross-
couple a wide range of carbonyl compounds with alcohols,
as well as with N- and S-nucleophiles. However, their pro-
tocol gave low yields with ketone substrates and could not
be extended to the preparation of branched dialkyl ethers,
despite the wide occurrence of these sterically congested
motifs in organic synthesis.
In this letter, we report that a Lewis acidic silane,
Me2SiHCl, can mediate the direct cross-coupling of a wide
range of carbonyl compounds with alcohols to form dialkyl
ethers, including sterically congested secondary-secondary
ethers.
As part of our program aiming at developing selective
reductions of oxygen-containing substrates using silanes
and Lewis acids,12 we undertook the development of a prac-
tical reductive cross-coupling of carbonyls and alcohols. As
a starting point, we selected the coupling of a ketone and a
primary alcohol, because this transformation is challenging
to accomplish using state of the art protocols (Table 1). Ac-
cordingly, when we applied the conditions reported by
Table 2 Alcohol Substrate Scopea
R3
Me
O
O
HO R3
+
H
Si Cl
+
R1
R2
R1
R2
MeCN
r.t., 12 h
Me
H
(1.1 equiv)
(1.1 equiv)
Entry
1
Product
Yield (%)
79
Entry
Product
Yield (%)
51
O
8
O
O
O
O
O
N
2
3
4
59
66
64
9
10
11
45
O
O
O
75 / 66d
O
O
82
O
O
O
5
52
12c
50
54
O
O
O
O
O
6
74
42
13c
7b
a Isolated yields; ketone (0.25 mmol).
b Crotyl alcohol (1.5 equiv), Me2SiHCl (2.0 equiv).
c 36 h.
d Ketone (25 mmol).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
Y. H. Lee, B. Morandi
Cluster
Synlett
Table 3 Carbonyl Substrate Scopea
We next explored the scope of functionalized alcohol
nucleophiles that can be employed under these reaction
conditions (Table 2). Initially, we were pleased to note that
esters, alkynes, alkenes and an imide were well tolerated
under these reaction conditions. On a larger scale (25 mmol
scale), the desired ether product was isolated with only a
slight decrease in yield (Table 2, Entry 10). Notably, ketones
reacted with sterically hindered secondary alcohols to form
highly congested ethers that cannot be easily accessed by
using alternative methods.1f,6b–c,7b–c,10b–c
Next, we explored the functional group tolerance of the
ketone substrates in the cross coupling with a sterically
crowded secondary alcohol (Table 3). Again, a broad range
of functional groups was tolerated, including a halogen,
alkene and a carbamate. The reaction could also be em-
ployed to chemo- and stereoselectively functionalize es-
trone.
Entry Carbonyl
Product
Yield
(%)
O
1
75
70
O
O
O
O
2
O
3
70
59
Cl
Cl
O
Lastly, we explored the possibility of using other hetero-
atom-based nucleophiles under our reaction conditions
(Table 4). A thiol and sulfonamide nucleophile afforded
good yield of the cross-coupled product. Finally, indole re-
acted selectively at the C3 position to give the correspond-
ing alkylated product in good yield.
O
O
4
N
O
N
O
O
In conclusion, we have reported a practical (one single
reagent) protocol for the reductive cross coupling of carbo-
nyls and alcohols.13,14 The reaction distinguishes itself by a
good functional group tolerance and the ability to obtain
sterically congested dialkyl ethers that are otherwise hard
to access. We are thus confident that this transformation
will find applications in organic synthesis.
5
76
54
O
O
O
6b
O
O
O
Table 4 Reductive Coupling of Carbonyls with S-, N-, and C-Nucleo-
H
philesa
7b,c
64
H
H
H
H
H
Me
Nu
H
O
HO
+
+
Nu
H
H
Si Cl
Me
HO
R1
R2
R1
R2
MeCN
r.t., 12 h
a For conditions see Table 2 and the Supporting Information. Isolated yields;
(1.1 equiv)
(1.1 equiv)
carbonyl (0.25 mmol).
b Me2SiHCl (2 equiv).
c 60 °C.
Entry
Nucleophile
Product
Yield (%)
69
SH
Roth and co-workers, only 22% of the desired product was
obtained, along with significant amounts of side-products
arising from ketone reduction and reductive dimerization.
Solvent optimization then revealed that acetonitrile could
improve the process, giving moderate yields of the product.
At this stage, we reasoned that utilizing a chlorosilane as
mediator might enable us to combine the benefits of a
Lewis acid and a silane into one reagent to improve the re-
activity. Gratifyingly, the use of just 1.1 equivalents of
Me2SiHCl led to product formation with a yield of 89%. In-
creasing the steric demand of the silane reagent had a nega-
tive impact on the reaction outcome, leading to reduced
conversions. Further control reactions confirmed that ace-
tonitrile is the solvent of choice for this transformation.
S
1
2
NH2
O
O
S O
HN
S
79
62
O
NH
H
N
3
a Isolated yields; ketone (0.25 mmol).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
Y. H. Lee, B. Morandi
Cluster
Synlett
Acknowledgment
(7) (a) Kalutharage, N.; Yi, C. S. Org. Lett. 2015, 17, 1778.
(b) Gooßen, L. J.; Linder, C. Synlett 2006, 3489. (c) Verhoef, M. J.;
Creyghton, E. J.; Peters, J. A.; van Bekkum, H. Chem. Commun.
1997, 1989.
(8) (a) Doyle, M. P.; DeBruyn, D. J.; Kooistra, D. A. J. Am. Chem. Soc.
1972, 94, 3659. (b) Wada, M.; Nagayama, S.; Mizutani, K.; Hiroi,
R.; Miyoshi, N. Chem. Lett. 2002, 31, 248. (c) Izumi, M.; Fukase,
K. Chem. Lett. 2005, 34, 594. (d) Iwanami, K.; Yano, K.; Oriyama,
T. Chem. Lett. 2007, 36, 38.
We thank the Max-Planck-Institut für Kohlenforschung, the Max
Planck Society, and the Fonds der Chemischen Industrien for funding.
Y. H. Lee thanks LG Chem for a doctoral fellowship. Professor Benja-
min List is acknowledged for sharing analytical equipment and chem-
icals. We further thank our NMR and MS services for technical
support.
(9) Gellert, B. A.; Kahlcke, N.; Feurer, M.; Roth, S. Chem. Eur. J. 2011,
17, 12203.
Supporting Information
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743. (b) Sassaman, M. B.; Kotian, K. D.; Prakash, G. K. S.; Olah, G.
A. J. Org. Chem. 1987, 52, 4314. (c) Kuethe, J. T.; Janey, J. M.;
Truppo, M.; Arredondo, J.; Li, T.; Yong, K.; He, S. Tetrahedron
2014, 70, 4563. (d) Hartz, N.; Prakash, G. K. S.; Olah, G. A. Synlett
1992, 569. (e) Hatakeyama, S.; Mori, H.; Kitano, K.; Yamada, H.;
Nishizawa, M. Tetrahedron Lett. 1994, 35, 4367. (f) Bajwa, J. S.;
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590838.
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u
p
p
ortioInfgrmoaitn
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p
p
ortiInfogrmoaitn
References and Notes
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(13) General procedure for the reductive etherification reaction:
To a mixture of carbonyl (0.25 mmol) and alcohol (0.275 mmol,
1.1 equiv) in acetonitrile (0.5 mL) was added chlorodimethyl-
silane (0.275 mmol, 1.1 equiv) under argon. The reaction
mixture was stirred at room temperature (ca. 25 °C) for 12 h.
The reaction was then quenched by adding a drop of aqueous
NaHCO3 solution under air. The resulting mixture was dried
over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (pentane/DCM or pentane/MTBE).
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12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenan-
1
thren-3-ol (Table 3, Entry 7): White solid. H NMR (500 MHz,
CDCl3): δ = 7.15 (d, J = 8.5 Hz, 1 H), 6.62 (dd, J = 8.5, 2.7 Hz, 1 H),
6.55 (d, J = 2.7 Hz, 1 H), 4.55 (s, 1 H), 3.49 (dd, J = 8.5, 8.5 Hz,
1 H), 3.32–3.23 (m, 1 H), 2.89–2.74 (m, 2 H), 2.31–2.21 (m, 1 H),
2.20–2.11 (m, 1 H), 2.06–1.93 (m, 2 H), 1.94–1.80 (m, 3 H),
1.79–1.69 (m, 2 H), 1.71–1.60 (m, 1 H), 1.58–1.42 (m, 3 H),
1.45–1.36 (m, 1 H), 1.39–1.10 (m, 9 H), 0.79 (s, 3 H). 13C NMR
(125 MHz, CDCl3): δ = 153.4, 138.5, 133.1, 126.7, 115.4, 112.7,
86.5, 77.1, 50.3, 44.2, 43.4, 38.8, 37.9, 33.3, 33.2, 29.8, 29.1, 27.3,
26.6, 26.0, 24.6, 24.5, 23.3, 11.9. HRMS (ESI+): m/z [M+H]+ calcd
for C24H35O2: 355.26316; found: 355.26335.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D