Synthesis of ethers from carbonyl compounds by reductive etherification catalyzed by iron(III) and silyl chloride

Article abstract of DOI:10.1055/s-0034-1380155

A simple iron- and silyl chloride catalyzed method for the preparation of symmetrical and nonsymmetrical ethers is presented. Various aldehydes and ketones were reductively etherified by using triethylsilane as a reducing agent in the presence of 2 mol% of iron(III) oxo acetate and 8 mol% of chloro(trimethyl)silane. The reactions can be carried out at ambient temperatures and pressures with ethyl acetate as the solvent.

Full text of DOI:10.1055/s-0034-1380155

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1749–1760
paper
1749
R. Savela, R. Leino
Paper
Synthesis
Synthesis of Ethers from Carbonyl Compounds by Reductive
Etherification Catalyzed by Iron(III) and Silyl Chloride
Risto Savela
Reko Leino*
Et3SiH (1.05 equiv)
Fe(III) oxo acetate (2.0 mol%)
Me3SiCl (8.0 mol%)
R1
R2
R1
R2
O
O
Laboratory of Organic Chemistry, Åbo Akademi University,
20500 Åbo, Finland
R1
R2
EtOAc
reko.leino@abo.fi
Received: 07.11.2014
Accepted after revision: 15.01.2015
Published online: 18.02.2015
These new methods circumvented the earlier problems,
at least to some degree, providing the isolated ethers in ac-
ceptable to good yields. The application of trimethylsilyl
triflate as a catalyst for ether synthesis was improved by
Olah and co-workers, who also extended the reaction to the
use of trimethylsilyl iodide as a separate catalyst.6 Several
other methods that use silanes or other compounds as re-
agents and/or catalysts in the syntheses of ethers have been
reported in recent decades. Among the catalysts that have
been used are boron trifluoride etherate,7 trimethylsilyl tri-
flate, trimethylsilyl iodide,8 bismuth(III) chloride, bis-
muth(III) bromide,9 indium(III) bromide,10 triflic acid, triflic
anhydride,11 solid acids or bases,12 molecular iodine,13 cop-
per(II) triflate,14 antimony(III) iodide,15 and zinc(II) tri-
flate.16
Iron-catalyzed reactions have been widely investigated
in recent years.17 In particular, the use of organosilanes as
reducing agents in combination with iron catalysts has gen-
erated significant attention.18 Of particular interest have
been various reduction reactions of carbonyl compounds to
alcohols;19 reductions of amides, imines, and cyano com-
pounds;20 and, recently, the reduction of sulfoxides to sul-
fides.21 Iron-catalyzed benzylations,21,22 one-pot reduc-
tion/chlorination reactions of benzylic carbonyl com-
pounds,23 and transformations of alcohols to azides have
also been reported.24 Two iron-catalyzed methods that use
organosilanes as reducing agents for synthesis of ethers
have recently emerged; these involve either reductive
etherifications of ketones, aldehydes, or alcohols,25 or the
reduction of the carbonyl groups of esters.26
DOI: 10.1055/s-0034-1380155; Art ID: ss-2014-z0682-op
Abstract A simple iron- and silyl chloride catalyzed method for the
preparation of symmetrical and nonsymmetrical ethers is presented.
Various aldehydes and ketones were reductively etherified by using tri-
ethylsilane as a reducing agent in the presence of 2 mol% of iron(III) oxo
acetate and 8 mol% of chloro(trimethyl)silane. The reactions can be car-
ried out at ambient temperatures and pressures with ethyl acetate as
the solvent.
Key words iron, catalysis, silicon, reductions, ethers, aldehydes, ke-
tones
The formation of C–O bonds is one of the oldest known
transformations in synthetic organic chemistry, the first
method dating back to 1850.1 In the Williamson ether syn-
thesis, an alkoxide is used to attack an alkyl halide. Some
years later, Wurtz developed a synthesis of dimethyl ether
from methyl iodide and silver oxide.2 Although it remains
one of the most widely used methods for preparing ethers,
the Williamson synthesis lacks generality, as it is only ap-
plicable to primary halides. With secondary halides, elimi-
nation and isomerization of the starting materials begin to
compete, leading to mixtures of products.
In the 1970s, in a series of papers, Doyle and co-workers
described acid-catalyzed etherifications of aldehydes in the
presence of silanes.3 However, the reported method has the
disadvantages of requiring a large excess of the silane and
the presence of an acid such as concentrated sulfuric acid or
trifluoroacetic acid. Later, Noyori reported the use of
trimethylsilyl triflate as a catalyst for the synthesis of
ethers from acetals or ketones, with trialkylsilanes acting as
the reducing agents.4 Subsequently, Mukaiyama and co-
workers reported the use of trityl perchlorate as a catalyst
for similar reactions.5
In our previous and ongoing work on iron-catalyzed
benzylation27 and chlorination28 of benzylic carbonyl com-
pounds, we frequently observed the formation of dibenzyl
ether derivatives as side products. As a result, we became
interested in investigating the potential extension of such
transformations to the synthesis of ethers. Here, we de-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1749–1760

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R. Savela, R. Leino
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Synthesis
Et3SiH
Fe(III) oxo acetate (cat.)
Me3SiCl (cat.)
Cl
O
O
EtOAc
1
1a
undesired
byproduct
Scheme 1 Synthesis of dibenzyl ether
Table 1 The Effects of Iron(III) Species and Chloro(trimethyl)silane as
Catalysts on the Reaction Time and Selectivity in the Synthesis of
Dibenzyl Ethera
scribe a condensation-type etherification of carbonyl com-
pounds in the presence of iron-based precatalysts in ethyl
acetate. In related transformations, previously reported by
Oriyama and co-workers, less-benign nitromethane was
used as the solvent.25
Fe(III) oxo acetate Me3SiCl
Time
(h)
Selectivity 1/1a Conv.
(mol%)
(equiv)
(%)b
In the present work, we made use of atmospherically
oxidized iron(II) acetate, which we refer to as ‘iron(III) oxo
acetate’. This known precatalyst is probably a trinuclear
iron complex with a central oxygen atom bridging three
iron(III) molecules. Such trinuclear metal acetate complex-
es have been used previously, and although various struc-
tural features have been proposed, no definite proof has
been presented of the exact structure of this particular
complex. A tentative structure is, however, shown in Figure 1.29
4.0
4.0
4.0
4.0
4.0
2.0
2.0
1.0
1.0
0.0
2.0
1.0
1
1
95:5
95:5
95:5
100:0
100:0
100:0
100:0
100:0
100:0
–
>99
>99
>99
>99
66c
>99
>99
>99
51
0.5
0.25
0.08
0.04
0.08
0.04
0.04
0.02
0.08
0.04
1
1
24
1
6
3
6
O
O
O
Fe
O
O
6
–
6
–
–
O
O
O
O
a Reactions conditions: PhCHO (2 mmol), Et3SiH (2.1 mmol), EtOAc (1 mL),
Fe
Fe
r.t.
O
O
b Determined by GC (FID).
O
O
c The catalyst dissolved very slowly under these conditions.
Figure 1 Tentative structure of iron(III) oxo acetate
On the basis of the optimization studies, we selected a
combination of 2.0 mol% of iron(III) oxo acetate and 8.0
mol% of chloro(trimethyl)silane as the preferred general
catalyst for further studies on the scope of the reaction. Our
initial investigations on the general substrate scope were
conducted on a 2 mmol scale by reacting aryl aldehydes to
form symmetrical ethers in short reaction times and good
to excellent yields (Table 2, entries 1–15). In two cases, the
reaction was scaled up to 10 mmol scale (entries 7 and 11),
and, in one case, it was scaled up to a 100 mmol scale (en-
try 6). In an attempt to introduce hydroxy substituents onto
the aromatic ring, we examined the reactions of para- and
ortho-hydroxy-substituted benzaldehydes. Although full
conversions of the starting materials were attained, the de-
sired reactivity was hampered, apparently, by activation of
the benzylic position, resulting in oligomerization, and only
in one case, that of the meta-substituted aldehyde, was the
desired product formed in a good yield (entry 11). However,
by protecting the hydroxy group as its acetyl derivative, the
para-product could also be obtained (Entry 12). When
cyano-, methoxy- or acetamido-substituted benzaldehyde
derivatives were used, only the starting material was ob-
In addition to iron(III) oxo acetate, we used
chloro(trimethyl)silane as a co-catalyst and triethylsilane
as the hydride source in ethyl acetate solution (Scheme 1).
First, we optimized the loadings of the iron(III) oxo ace-
tate and chloro(trimethyl)silane catalysts to provide a satis-
factory selectivity between the desired dibenzyl ether (1)
and the undesired byproduct benzyl chloride (1a) with
practical reaction times and conditions. The use of a signifi-
cant excess of chloro(trimethyl)silane resulted in the for-
mation of small amounts of benzyl chloride, whereas the
use of less than 0.1 equivalents of chloro(trimethyl)silane
suppressed the formation of the byproduct. Our complete
results are listed in Table 1.
The presence of both precatalysts, iron(III) oxo acetate
and chloro(trimethyl)silane, was necessary for the reaction
to proceed. In the absence of either of these compounds, no
ether formation was observed. The rate of the reaction was
influenced to
a greater degree by the loading of
chloro(trimethyl)silane than by that of iron(III) oxo acetate.
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R. Savela, R. Leino
Paper
Synthesis
served, even after prolonged reaction times. We also briefly
examined the etherification of some nonbenzylic ketones
and aldehydes (entries 16–19). Whereas no reactivity was
observed with iron(III) oxo acetate as the catalyst, good
yields of the desired ethers were obtained on switching to
iron(III) chloride. Citronellal was also investigated as a
starting material, but in this case, the reaction gave signifi-
cant amounts of pulegol isomers and a nonseparable mix-
ture of ethers.
Next, we examined the preparation of nonsymmetrical
ethers by using trimethylsilylated alcohols in combination
with aldehyde derivatives (Scheme 2).
Et3SiH (1.05 equiv)
Fe(III) oxo acetate
or FeCl3 (2 mol%)
R1
O
O
Me3SiCl (8 mol%)
R3
+
R3OSiMe3
R1
R2
R2
EtOAc
Scheme 2 Synthesis of unsymmetrical ethers
Table 2 Etherification of Aldehydes and Ketonesa
The results are collected in Table 3. Whereas good yields
were observed in all reactions within one hour at room
temperature, small amounts of the corresponding symmet-
rical ethers were produced when aliphatic ketones or alde-
hydes were used in combination with (benzyloxy)(trimeth-
yl)silane (entries 6 and 7). This issue could, however, be re-
solved by reversing the roles of the reagents (entries 8–11).
The reaction of hexanal with cyclohexyloxy(trimethyl)si-
lane resulted in the formation of various side products that
could not be separated from the desired product. This again
could be resolved by treating the primary trimethylsilylated
alcohol with the corresponding ketone (entries 12 and 13).
When (–)-menthyl trimethylsilyl ether was treated with
benzaldehyde or biphenyl-4-carboxaldehyde, the desired
ether products were formed within 30 minutes, with reten-
tion of configuration at all stereocenters (entries 14 and
15). As in the case of trimethylsilylated alcohols, the use of
acetophenones led to mixtures of the desired nonsymmet-
rical ether and small amounts of the undesired symmetri-
cal ether, as well as to reductive halogenation of the ace-
tophenone. Full conversions of the starting material could
only be attained by increasing the amount of
chloro(trimethyl)silane, which in turn shifted the reaction
towards reductive halogenation of the acetophenone.
Finally, whereas the approach using α,β-unsaturated al-
dehydes and ketones for the preparation of symmetrical
ethers failed, the reaction of (allyloxy)(trimethyl)silane in
combination with benzylic aldehydes or adamantan-2-one
gave the desired ethers in good yields (entries 16–18), al-
though concomitant isomerization of the allylic double
bond to a vinylic double bond was observed to a minor de-
gree.
Entry Substrate
Time
Product
Yieldb
(%)
130
231
332
433
516
6
PhCHO
1 h
1 h
1 h
1 h
1 h
2 h
2 h
3 h
3 h
1
2
3
4
5
6
7
8
9
Bn2O
93
76
92
98
64
75c
75d
97
96
73
77
68
63d
4-TolCHO
(4-TolCH2)2O
2-TolCHO
(2-TolCH2)2O
4-t-BuC6H4CHO
4-ClC6H4CHO
2-ClC6H4CHO
2,4-Cl2C6H3CHO
4-FC6H4CHO
4-F3CC6H4CHO
4-BrC6H4CHO
3-HOC6H4CHO
4-AcOC6H4CHO
2-O2NC6H4CHO
4-MeO2CC6H4CHO
4-PhC6H4CHO
(4-t-BuC6H4CH2)2O
(4-ClC6H4CH2)2O
(2-ClC6H4CH2)2O
(2,4-Cl2C6H3CH2)2O
(4-FC6H4CH2)2O
(4-F3CC6H4CH2)2O
(4-BrC6H4CH2)2O
(3-HOC6H4CH2)2O
(4-AcOC6H4CH2)2O
(2-O2NC6H4CH2)2O
7
834
935
1036
11
1.5 h 10
1 h
2 h
2 h
1 h
1 h
5 h
11
12
13
14
15
16
1237
1338
1439
15
(4-MeO2CC6H4CH2)2O 79
(4-PhC6H4CH2)2O
Cy2O
89
84
83
94
64
16e,40 cyclohexanone
17e,11c CyCHO
15 min 17
(CyCH2)2O
18e,11c Me(CH2)4CHO
1 h
3 h
18
19
[Me(CH2)5]2O
[CyCH(Me)]2O
19e
CyCOMe
a Reaction conditions: carbonyl compound (2 mmol), Et3SiH (2.1 mmol),
Fe(III) oxo acetate (2.0 mol%), Me3SiCl (8 mol%), EtOAc (1 mL), r.t.
b Isolated yield.
c Reaction carried out on a 100 mmol scale
d Reaction carried out on a 10 mmol scale.
e FeCl3 was used instead of Fe(III) oxo acetate.
When acetophenone derivatives were used as starting
materials, they gave only traces of the corresponding ethers
with concomitant formation of small amounts of the corre-
sponding halogenated products, formed through consump-
tion of the chloro(trimethyl)silane catalyst. 1-Phenylbu-
tane-1,3-dione and 1,3-diphenylacetone similarly showed
no reactivity, whereas benzophenone only underwent a
slow Clemmens-type reduction. Finally, α,β-unsaturated
ketones and aldehydes were also tested as starting materi-
als, but no reactions were observed by GC monitoring.
Baba and co-workers have suggested a tentative mecha-
nism for the Lewis acid catalyzed derivatization of carbonyl
compounds in combination with silyl halides.51,52 A similar
mechanistic interpretation was included in our preceding
work on the arylation of aromatic carbonyl compounds27
and the halogenation of carbonyl compounds.28 In accor-
dance with previously postulated reaction mechanisms for
similar reactions,5,6,11c,53 the present reaction probably pro-
ceeds through initial activation of either the trimethylsilyl
chloride or the iron(III) species in question, followed by co-
ordination of the carbonyl group to either an iron or a sili-
con species. The use of trimethylsilyl iodide or trimethylsi-
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1752
R. Savela, R. Leino
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Synthesis
lyl triflate as the catalyst4,11 supports coordination to a sili-
con species with subsequent silylium ion-type catalysis.54
The complex formed might undergo hydrosilylation and
subsequent SN2-type addition of the second carbonyl com-
pound with transfer of a siloxy moiety to the attacking car-
bonyl carbon. The existence of an SN2-type reaction is also
supported by the full retention of the stereocenters in prod-
ucts 32 and 33. The acetal that is formed is subsequently re-
duced to the desired ether. A tentative catalytic cycle is
shown in Scheme 3.
To conclude, we have developed a robust method for the
production of symmetrical and unsymmetrical ethers un-
der mild conditions in a benign solvent. This method might
prove applicable to syntheses of important building blocks
for pharmaceuticals or, for example, to methods for the in-
troduction of benzyl ether protecting groups.
All chemicals were purchased from commercial sources and used
without further purification unless otherwise mentioned. FeCl3 was
obtained from Sigma Aldrich (97% purity). Similar reactivities were
observed in selected test reactions using higher grade FeCl3 (99.99%,
Sigma Aldrich). Test reactions under similar conditions using palladi-
Table 3 Ethers from Trimethylsilylated Alcoholsa
Entry
Reactants
Time(h)
Product
Yieldc (%)
125a
2c,41
3c,42
443
4-BrC6H4CHO
4-F3CC6H4CHO
2-O2NC6H4CHO
4-TolCHO
1
20
21
22
23
24
25
4-BrC6H4CH2OBn
4-F3CC6H4CH2OBn
2-O2NC6H4CH2OBn
4-TolCH2OBn
79
89
77
89
83
78
85
87
80
80
85
90
77
1
1
BnOSiMe3
1
544
3-HOC6H4CHO
Me(CH2)4CHO
cyclohexanone
PhCHO
1
3-HOC6H4CH2OBn
Me(CH2)5OBn
645
1d
746
1d
CyOBn
26
845
0.5d
0.5d
0.5d
0.5d
0.5d
0.5d
CyOBn
945
4-TolCHO
27
28
29
30
31
4-TolCH2OCy
CyOSiMe3
1045
1147
126
1348
4-MeO2CC6H4CHO
4-PhC6H4CHO
cyclohexanone
i-BuCOMe
4-MeO2CC6H4CH2OCy
4-PhC6H4CH2OCy
Me(CH2)7OCy
Me(CH2)7OSiMe3
i-BuCH(Me)O(CH2)7Me
1445
PhCHO
0.5d
32
33
88
76
O
O
Ph
OSiMe3
1547
4-PhC6H4CHO
0.5d
Ph
1649
1734
PhCHO
0.5d
0.5d
34
35
BnOAll
80
92
4-FC6H4CHO
4-FC6H4CH2OAll
AllOSiMe3
O
O
1850
0.5d
36
72
a Reaction conditions: trimethylsilyl ether (1.0 mmol), carbonyl compound (1.0 mmol), Et3SiH (1.05 mmol), Fe(III) oxo acetate (2.0 mol%), Me3SiCl [0.08 equiv
(from 2 mmol)].
b Isolated yield.
c Reaction performed on a 5 mmol scale.
d FeCl3 was used instead of Fe(III) oxo acetate.
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R. Savela, R. Leino
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Synthesis
ClSiMe3
Fe(III) salt
Optimization of the Reaction of Benzaldehyde (1) with Triethylsi-
lane
O
Et3Si
R1
The desired amount of iron(III) oxo acetate (iron content 31.25%) was
suspended in EtOAc (1.0 mL) and the corresponding amount of
Me3SiCl was added, resulting in dissolution of the iron salt. PhCHO
(0.2 mL, 2.0 mmol) and Et3SiH (0.34 mL, 2.1 mmol) were added se-
quentially, and the resulting solution was stirred for up to 6 h at r.t.
while the reaction was monitored hourly by GC/FID.
SiEt3
R2
R1
O
O
Fe(III)
Cl SiMe3
Et3SiH
Preparation of Catalyst Stock Solution
Iron (III) oxo acetate (oxidized at r.t.: 70 mg, 0.3 mmol; oxidized at
110 °C for 24 h: 64.5 mg, 0.3 mmol) or FeCl3 (45 mg, 0.3 mmol) was
suspended in EtOAc (~5 ml) in a 10 mL volumetric flask, and Me3SiCl
(0.2 mL, 1.6 mmol) was added. When the iron salt had dissolved,
EtOAc was added to adjust the total volume to 10 mL.
Fe(III)
Cl SiMe3
or
Fe(III)
Cl SiMe3
[SiClFe]
R1
SiEt3
O
O
O
R1
R1
O
R2
Reductive Etherification; General Method
The appropriate reactant (2 mmol) and Et3SiH (0.34 mL, 2.1 mmol)
were successively added to the stock solution of catalysts (1.0 mL),
and the mixture was stirred at r.t. until full conversion was attained.
The mixture was then diluted with EtOAc (10 mL) and washed with
sat. aq NaHCO3 (2 × 3 mL). The aqueous phase was washed with EtOAc
(3 mL), and then the organic phases were combined, dried (Na2SO4),
and evaporated to dryness. The resulting crude product was purified
by flash chromatography or by crystallization.
[FeClSi]
Et3Si
Et3SiH
O
R1
O
R2
Scheme 3 Tentative catalytic cycle for the reductive etherification re-
action
Dibenzyl Ether (1)
Prepared according to the general method with a reaction time of 1 h
and workup in hexane. The crude product was purified by flash chro-
matography (silica gel, gradient 0–35% hexane–EtOAc) to give a color-
less liquid; yield: 185 mg (93%); Rf = 0.67 (EtOAc–hexane, 1:4); puri-
ty: >99%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.41–7.36 (m, 8 H), 7.33–
7.30 (m, 2 H), 4.58 (s, 4 H).
um black, PdCl2, CuCl2, or NiI2 as the catalyst did not result in any de-
tectable formation of ether products. NMR spectra were recorded by
using 600 MHz and 500 MHz Bruker spectrometers. The 600 MHz
spectrometer was equipped with a BBI-5mm-Zgrad-ATM probe or a
BBO-5mm-Zgrad probe at 298 K and was operated at 600.13 MHz for
1H and 150.92 for 13C. The 500 MHz spectrometer was equipped with
a BBI-5mm-Zgrad-ATM probe or a BBO-5mm-Zgrad probe at 298 K
and was operated at 500.13 MHz for 1H and 125.76 for 13C. The NMR
spectra were calibrated to the solvent peak.
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 139.0, 128.7, 128.1, 127.9,
72.6.
The product distribution and the purity were monitored by GC/FID
using an Agilent GC chromatograph equipped with an HP-1 column
(30 μm × 320 mm × 0.25 μm) with H2 as carrier gas. The chromato-
graph was operated with the following temperature program: injec-
tor 220 °C, oven Tinitial = 50 °C (2 min), rate 10 °C/min, Tfinal = 300 °C,
hold 2 min. Trimethylsilylation reactions of BnOH, CyOH, (–)-men-
thol, and octan-1-ol were carried out as described previously.55 For
product 19, the dr was verified by GC/FID. For products 32 and 33, the
dr and er were verified by GC/FID in combination with information
on the coupling constants from the 1H NMR and reference spectra.
Bis(4-methylbenzyl) Ether (2)
Prepared according to the general method with a reaction time of 1 h
and workup in hexane. The crude product was purified by flash chro-
matography (silica gel, gradient 0–35% hexane–EtOAc) to give a white
solid that was crystallized (hexane) to provide white crystals; yield:
171 mg (76%); mp 62 °C (lit.17 61–62 °C); Rf = 0.67 (EtOAc–hexane,
1:4); purity: >99%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.25 (d, J = 8.0 Hz, 4 H), 7.17
(d, J = 8.0 Hz, 4 H), 4.50 (s, 4 H), 2.35 (s, 6 H).
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 137.7, 136.0, 129.3, 128.2,
72.3, 21.3.
Iron(III) Oxo Acetate Catalyst
The oxidized Fe(III) oxo acetate catalyst used in the reactions was re-
producibly prepared from Fe(OAc)2 (Sigma Aldrich; 99.99% purity) by
solid-state oxidization under ambient conditions over a prolonged
period of time or at 110 °C for 24 or 72 h. The prepared catalysts were
characterized by IR spectroscopy, elemental analysis, Mössbauer
spectroscopy, and inductively coupled plasma (ICP) techniques to ver-
ify and determine their iron(III) contents. (For details, see Supporting
Information.) The iron(III) oxo acetate samples used in this work were
prepared at r.t. or at 110 °C for 24 h, and had iron contents of 31.25%
and 34.64%, respectively (ICP).
Bis(2-methylbenzyl) Ether (3)
Prepared according to the general method with a reaction time of 1 h
and workup in hexane. The crude product was purified by flash chro-
matography (silica gel, gradient 0–35% hexane–EtOAc) to give a white
solid that was crystallized (hexane) to provide white needles; yield:
208 mg (92%); mp 50–51 °C (lit.56 51–52 °C); Rf = 0.7 (EtOAc–hexane,
1:4); purity: >99%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.38–7.36 (m, 2 H), 7.23–
7.18 (m, 6 H), 4.58 (s, 4 H), 2.34 (s, 6 H).
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13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 137.1, 136.9, 130.5, 128.9,
128.1, 126.1, 71.1, 18.9.
13C NMR (125.76 MHz, CD2Cl2, 25 °C): 139.0, 132.7, 131.8, 130.8,
129.8, 127.3, 71.4.
Anal. Calcd for C14H10Cl4O: C, 50.04%; H, 3.00%. Found: C, 50.07%; H,
2.99%.
Bis(4-tert-butylbenzyl) Ether (4)
Prepared according to the general method with a reaction time of 1 h
and workup in hexane. The crude product was purified by flash chro-
matography (silica gel, gradient 0–35% hexane–EtOAc) to give a color-
less liquid; yield: 303 mg (98%); Rf = 0.8 (EtOAc–hexane, 1:4); purity:
99%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.39 (ddd, J = 2.1, 8.5 Hz, 4
H), 7.30 (ddd, J = 2.1, 8.5 Hz, 4 H), 4.52 (s, 4 H), 1.33 (s, 18 H).
Bis(4-fluorobenzyl) Ether (8)
Prepared according to the general method with a reaction time of 3 h
and workup in EtOAc. The crude product was purified by flash chro-
matography (silica gel, gradient 0–35% hexane–EtOAc) to give a color-
less liquid; yield: 227 mg (97%); Rf = 0.67 (EtOAc–hexane, 1:4); puri-
ty: >99%.
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 151.0, 136.1, 127.9, 125.6,
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.35 (m, 4 H), 7.06 (tt, J = 2.5,
72.3, 34.8, 31.5.
9.1 Hz, 4 H), 4.51 (s, 4 H).
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 162.7 (d, JC,F = 245 Hz),
134.8 (d, JC,F = 3 Hz), 129.9 (d, JC,F = 9 Hz), 115.5 (d, JC,F = 22 Hz), 71.8.
Bis(4-chlorobenzyl) Ether (5)
Prepared according to the general method with a reaction time of 1 h
and workup in EtOAc. The crude product was purified by flash chro-
matography (silica gel, gradient 0–35% hexane–EtOAc) to give a white
solid; yield: 172 mg (64%); Rf = 0.45 (EtOAc–hexane, 1:4); purity: 99%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.35–7.30 (m, 8 H), 4.52 (s, 4
H).
Bis[4-(trifluoromethyl)benzyl] Ether (9)
Prepared according to the general method with a reaction time of 3 h
and workup in EtOAc. The crude product was purified by flash chro-
matography (silica gel, gradient 0–35% hexane–EtOAc) to give a color-
less liquid; yield: 320 mg (96%); Rf = 0.67 (EtOAc–hexane, 1:4); puri-
ty: 99%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.64 (d, J = 8.0 Hz, 4 H), 7.52
(d, J = 8.0 Hz, 4 H), 4.66 (s, 4 H).
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 137.4, 133.6, 129.5, 128.8,
71.8.
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 143.0, 130.0 (q, JC,F = 32 Hz),
128.1, 125.7 (q, JC,F = 4 Hz), 124.8 (q, JC,F = 272 Hz), 72.1.
Bis(2-chlorobenzyl) Ether (6)
2-Chlorobenzaldehyde (14.1 g, 100 mmol) and Fe(III) oxo acetate
(0.45 g, 2 mmol) were dissolved in EtOAc (100 mL). Me3SiCl (1 mL, 8
mmol) was added, and the mixture was stirred at r.t. until the Fe(III)
oxo acetate dissolved (~5 min). Et3SiH (17 mL, 105 mmol) was then
added, resulting in spontaneous refluxing for ~5 min. The solution
was stirred for 1 h at r.t., EtOAc (50 mL) was added, and the mixture
was washed with sat. aq NaHCO3 (2 × 30 mL). The aqueous phases
were combined and washed with EtOAc (30 mL), and the organic
phases were then combined and dried (Na2SO4). The crude product
was purified by crystallization (EtOH, –18 °C) to give white crystals;
yield: 10.0 g (75%); mp 48–49 °C (lit.57 48–49 °C); purity: 98%.
Bis(4-bromobenzyl) Ether (10)
Prepared according to the general method with a reaction time of 1.5
h and workup in EtOAc. The crude product was purified by crystalli-
zation from hexane to give white needles; yield: 259 mg (73%); mp
84 °C (lit.58 84.5–85.5 °C); purity: 98%.
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 7.49 (td, J = 2.2, 8.7 Hz, 4 H),
7.25 (d, J = 8.7 Hz, 4 H), 4.50 (s, 4 H).
13C NMR (125.75 MHz, CD2Cl2, 25 °C): δ = 137.8, 131.8, 129.8, 121.7,
71.8.
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 7.58–7.56 (m, 2 H), 7.38 (dd,
J = 1.5, 7.6 Hz, 2 H), 7.31 (ddd, J = 1.5, 7.6 Hz, 2 H), 7.26 (ddd, J = 1.8,
7.6 Hz, 2 H), 4.74 (s, 4 H).
4,4′-[Oxydi(methylene)]diphenol (11)
Prepared according to the general method with a reaction time of 1 h
and workup in EtOAc. The crude product was purified by flash chro-
matography (silica gel, gradient 20–80% hexane–EtOAc) to give a
thick colorless liquid containing a small amount of residual EtOAc as
an impurity that could not be removed; yield: 176 mg (77%);59 Rf =
0.63 (EtOAc–hexane, 1:1).
13C NMR (125.76 MHz, CD2Cl2, 25 °C): δ = 136.4, 133.2, 129.6, 129.5,
129.2, 70.2.
Anal. Calcd for C14H12Cl2O: C, 62.94%; H, 4.53%. Found: C, 62.98%; H,
4.53%.
Bis(3,4-dichlorobenzyl) Ether (7)
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.19 (t, J = 7.8 Hz, 2 H), 6.89
3,4-Dichlorobenzaldehyde (1.75 g, 10 mmol) was dissolved in the cat-
alyst stock solution (5 mL). Et3SiH (1.7 mL, 10.5 mmol) was added,
and the mixture was stirred at r.t. for 2 h. EtOAc (30 mL) was then
added and the resulting solution was washed with sat. aq NaHCO3
(2 × 10 mL). The aqueous phases were combined and washed with
EtOAc (10 mL), and then the organic phases were combined and dried
(Na2SO4). The crude product was purified by flash chromatography
(silica gel, gradient 0–35% EtOAc–hexane) to give a white solid that
was crystallized (hexane) to provide white needles; yield: 1.26 g
(75%); mp 61 °C; Rf = 0.52 (EtOAc–hexane, 1:4); purity: > 99%.
(m, 2 H), 6.84 (m, 2 H), 6.74 (m, 2 H), 5.81 (br s, 2 H), 4.50 (s, 4 H).
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 156.3, 140.2, 130.0, 120.4,
115.1, 115.0, 72.2.
Oxybis(methylene-4,1-phenylene) Diacetate (12)
Prepared according to the general method with a reaction time of 2 h
and workup in CH2Cl2. The crude product was purified by flash chro-
matography (silica gel, gradient 0–80% hexane–EtOAc) to give a white
solid; yield: 214 mg (68%); mp 109–110 °C (Lit.37 113–114 °C); Rf =
0.19 (EtOAc–hexane, 1:4); purity >99%.
1H NMR (500.13 MHz, CD2Cl2, 25 °C): 7.47 (d, J = 2.0 Hz, 2 H), 7.44 (d,
J = 8.2 Hz, 2 H) 7.22–7.20 (m, 2 H), 4.51 (s, 4 H).
1H NMR (500.13 MHz, CD2Cl2, 25 °C): 7.40–7.37 (m, 4 H), 7.07 (td, J =
2.4, 9.0 Hz, 4 H), 4.56 (s, 4 H), 2.28 (s, 6 H).
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13C NMR (125.76 MHz, CD2Cl2, 25 °C): 169.8, 150.6, 136.5, 129.0,
122.0, 71.9, 21.3.
Dihexyl Ether (18)
Prepared according to the general method with FeCl3 as the catalyst, a
reaction time of 1 h, and workup in hexane. The crude product was
purified by flash chromatography (silica gel, gradient 0–35% hexane–
EtOAc) to give a colorless liquid; yield: 174 mg (94%); Rf = 0.86
(EtOAc–hexane, 1:4); purity: 97%.
1H NMR (600.13 MHz, CDCl3, 25 °C): δ = 3.38 (t, J = 6.8 Hz, 4 H), 1.58–
1.53 (m, 4 H), 1.35–1.24 (m, 12 H), 0.88 (t, J = 7.1 Hz, 6 H).
Bis(2-nitrobenzyl) Ether (13)
2-Nitrobenzaldehyde (1.5 g, 10 mmol) was dissolved in the stock cat-
alyst solution (5 mL). Et3SiH (1.7 mL, 10.5 mmol) was added, and the
mixture was stirred for 2 h. The solution was filtered and the filtrate
was discarded. The off-white solid residue was crystallized (EtOAc) to
give white crystals; yield: 0.9 g (63%); mp 160 °C (lit.38 160.5–161 °C);
purity: >99%.
13C NMR (150.92 MHz, CDCl3, 25 °C): δ = 71.1, 31.9, 29.9, 26.0, 22.8,
14.2.
1H NMR (600.13 MHz, DMSO, 25 °C): δ = 8.08 (d, J = 7.9 Hz, 2 H), 7.81–
7.78 (m, 4 H), 7.62–7.57 (m, 2 H), 4.96 (s, 4 H).
13C NMR (150.92 MHz, DMSO, 25 °C): δ = 147.3, 134.0, 133.7, 128.81,
128.76, 124.6, 68.8.
Bis(1-cyclohexylethyl) Ether (19)
Prepared according to the general method with FeCl3 as the catalyst, a
reaction time of 3 h, and workup in hexane. The crude product was
purified by flash chromatography (silica gel, gradient 0–35% hexane–
EtOAc), resulting in partial separation of the diastereomers as color-
less liquids.
Dimethyl 4,4′-[Oxydi(methylene)]dibenzoate (14)
Prepared according to the general method with a reaction time of 1 h
and workup in CH2Cl2. The crude product was purified by trituration
in hexane for 2 h to give a white powder; yield: 79% (249 mg); mp
108–110 °C; purity: 98%.
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 8.01 (d, J = 8.5 Hz, 4 H), 7.46
(d, J = 8.5 Hz, 4 H), 5.32 (s, 4 H), 3.89 (s, 6 H).
Fraction 1
Yield: 65 mg (27%); Rf = 0.91 (EtOAc–hexane, 1:9); purity: 98%; dr
100:0.
1H NMR (500.13 MHz, CDCl3, 25 °C): δ = 3.11 (quint, J = 6.2 Hz, 2 H),
1.89–1.84 (m, 2 H), 1.74–1.61 (m, 8 H), 1.33–1.08 (m, 8 H), 1.02 (d, J =
6.2 Hz, 6 H), 1.01–0.87 (m, 4 H).
13C NMR (125.75 MHz, CD2Cl2, 25 °C): δ = 167.1, 143.9, 129.9, 127.7,
72.2, 52.3.
13C NMR (125.75 MHz, CDCl3, 25 °C): δ = 76.5, 43.1, 28.7, 28.1, 26.0,
25.7, 25.6, 16.2.
Bis(4-biphenylmethyl) Ether (15)
Fraction 2
Prepared according to the general method with a reaction time of 1 h
and workup in EtOAc. After 45 min, EtOAc (1 mL) was added and the
mixture was stirred for additional 15 min. The crude product was pu-
rified by crystallization (EtOH) to give white crystals; yield: 312 mg
(89%); mp 87 °C (lit.60 87–89 °C); purity: >99%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.64–7.62 (m, 8 H), 7.49–
7.44 (m, 8 H), 7.36 (tt, J = 1.3, 7.5 Hz, 2 H), 4.64 (s, 4 H).
Yield: 88 mg (37%); Rf = 0.87 (EtOAc–hexane, 1:9); purity: >99%; dr:
10:90.
1H NMR (500.13 MHz, CDCl3, 25 °C): δ (major diastereomer) = 3.15
(quint, J = 6.2 Hz, 2 H), 1.85–1.79, (m, 2 H), 1.76–1.62 (m, 8 H), 1.38–
1.31 (m, 2 H), 1.27–1.10 (m, 6 H), 1.05 (d, J = 6.2 Hz, 6 H), 1.00–0.90
(m, 4 H).
13C NMR (125.75 MHz, CDCl3, 25 °C): δ (major diastereomer) = 78.1,
43.7, 29.6, 28.6, 26.9, 26.61, 26.57, 17.9.
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 141.2, 140.8, 138.1, 129.2,
128.6, 127.7, 127.41, 127.38, 72.3.
Anal. Calcd for C26H22O: C, 89.1%; H, 6.3%. Found: C, 89.2%; H, 6.3%.
Benzyl 4-Bromobenzyl Ether (20)
BnOSiMe3 (0.18 g, 1 mmol), 4-bromobenzaldehyde (0.19 g, 1 mmol),
and Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the stock cata-
lyst solution (1 mL) was added, and the mixture was stirred for 1 h.
EtOAc (10 mL) was added and the mixture was washed with sat. aq
NaHCO3 (2 × 3 mL). The aqueous phases were combined and washed
with EtOAc (3 mL), and then the organic phases were combined and
dried (Na2SO4). The crude product was purified by flash chromatogra-
phy (silica gel, gradient 0–35% EtOAc–hexane) to give a colorless oil;
yield: 219 mg (79%); Rf = 0.68 (EtOAc–hexane, 1:4); purity: 98%.
Dicyclohexyl Ether (16)
Prepared according to the general method with FeCl3 as the catalyst, a
reaction time of 5 h, and workup in hexane. The crude product was
purified by flash chromatography (silica gel, gradient 0–35% hexane–
EtOAc) to give a colorless liquid; yield: 182 mg (84%); Rf = 0.77
(EtOAc–hexane, 1:4); purity: 95%.
1H NMR (600.13 MHz, CDCl3, 25 °C): δ = 3.33–3.28 (m, 2 H), 1.87–1.83
(m, 4 H), 1.75–1.70 (m, 4 H), 1.54–1.51 (m, 2 H), 1.27–1.11 (m, 10 H).
13C NMR (150.92 MHz, CDCl3, 25 °C): δ = 74.8, 33.5, 26.0, 24.7.
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 7.50 (ddd, J = 2.2, 8.8 Hz, 2
H), 7.38–7.35 (m, 4 H), 7.34–7.25 (m, 3 H), 4.56 (s, 2 H), 4.52 (s, 2 H).
13C NMR (125.75 MHz, CD2Cl2, 25 °C): δ = 138.7, 138.1, 131.8, 129.7,
Bis(cyclohexylmethyl) Ether (17)
128.7, 128.1, 128.0, 121.6, 72.6, 71.7.
Prepared according to the general method with FeCl3 as the catalyst, a
reaction time of 15 min, and workup in hexane. The crude product
was purified by flash chromatography (silica gel, gradient 0–35%
hexane–EtOAc) to give a colorless liquid; yield: 178 mg (83%); Rf =
0.84 (EtOAc–hexane, 1:4); purity: 93%.
1H NMR (600.13 MHz, CDCl3, 25 °C): δ = 3.17 (d, J = 6.7 Hz, 4 H), 1.76–
1.63 (m, 10 H), 1.60–1.53 (m, 2 H), 1.23 (tq, J = 3.2, 12.3 Hz, 4 H), 1.15
(tq, J = 3.2, 12.3 Hz, 2 H), 0.90 (dq, J = 3.2, 12.3 Hz, 4 H).
Benzyl 4-(Trifluoromethyl)benzyl Ether (21)
BnOSiMe3 (0.9 g, 5 mmol), 4-(trifluoromethyl)benzaldehyde (0.68
mL, 5 mmol), and Et3SiH (0.84 mL, 5.25 mmol) were mixed together,
the stock catalyst solution (5 mL) was added, and the mixture was
stirred for 1 h. EtOAc (20 mL) was then added and the solution was
washed with sat. aq NaHCO3 (2 × 8 mL). The aqueous phases were
combined and washed with EtOAc (8 mL), and then the organic
phases were combined and dried (Na2SO4). The crude product was
13C NMR (150.92 MHz, CDCl3, 25 °C): 77.2, 38.2, 30.3, 26.9, 26.1.
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purified by flash chromatography (silica gel, gradient 0–35% EtOAc–
hexane) to give a colorless oil; yield: 1.18 g (89%); Rf = 0.75 (EtOAc–
hexane, 1:4); purity: 97%.
13C NMR (125.76 MHz, CD2Cl2, 25 °C): δ = 156.3, 140.7, 138.7, 129.9,
128.7, 128.2, 128.0, 120.2, 114.85, 114.82, 72.5, 72.2.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.64 (d, J = 8.1 Hz, 2 H), 7.52
(d, J = 8.1 Hz, 2 H), 7.41–737 (m, 4 H), 7.34–7.31 (m, 1 H), 4.64 (s, 2 H),
4.60 (s, 2 H).
Benzyl Hexyl Ether (25)
BnOSiMe3 (0.21 g, 1.15 mmol), hexanal (0.12 ml, 1 mmol), and Et3SiH
(0.17 mL, 1.05 mmol) were mixed together, the stock catalyst solution
prepared from FeCl3 (1 mL) was added, and the mixture was stirred
for 1 h. EtOAc (10 mL) was added, and the mixture was washed with
sat. aq NaHCO3 (3 mL). The aqueous phases were combined and
washed with EtOAc (2 × 3 mL), and then the organic phases were
combined and dried (Na2SO4). The crude product was purified by
flash chromatography (silica gel, gradient 0–35% EtOAc–hexane) to
give a colorless oil; yield: 150 mg (78%); Rf = 0.8 (EtOAc–hexane, 1:4);
purity: 94%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.38–7.33 (m, 4 H), 7.30–
7.26 (m, 1 H), 4.48 (s, 2 H), 3.47 (t, J = 6.6 Hz, 2 H), 1.63–1.58 (m, 2 H)
1.40–1.27 (m, 6 H), 0.91 (t, J = 7.1 Hz, 3 H).
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 139.5, 128.6, 127.9, 127.7,
73.1, 71.0, 32.2, 30.2, 26.3, 23.1, 14.3.
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 143.4, 138.6, 129.8 (q, JC,F
32 Hz), 128.8, 128.2, 128.1, 128.0, 125.6 (q, JC,F = 4 Hz), 124.8 (q, JC,F
272 Hz), 73.0, 71.7.
=
=
Benzyl 2-Nitrobenzyl Ether (22)
BnOSiMe3 (0.9 g, 5 mmol), 2-nitrobenzaldehyde (0.76 g, 5 mmol), and
Et3SiH (0.84 mL, 5.25 mmol) were mixed, the stock catalyst solution
(5 mL) was added, and the mixture was stirred for 1 h. EtOAc (20 mL)
was then added and the mixture was washed with sat. aq NaHCO3 (2
× 8 mL). The aqueous phases were combined and washed with EtOAc
(8 mL), and then the organic phases were combined and dried
(Na2SO4). The crude product was purified by flash chromatography
(silica gel, gradient 0–50% EtOAc–hexane) to give a white to pale-yel-
low solid that was crystallized (hexane) to provide white needles;
yield: 0.94 g (77%); mp 58–59 °C (lit.61 64–66 °C); Rf = 0.49 (EtOAc–
hexane, 1:4); purity: 97%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 8.05 (dd, J = 1.3, 8.1 Hz, 1 H),
7.87–7.85 (m, 1 H), 7.67–7.66 (m, 1 H), 7.48–7.45 (m, 1 H), 7.41–7.36
(m, 4 H), 7.33–7.30 (m, 1 H), 4.94 (s, 2 H), 4.66 (s, 2 H).
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 147.8, 138.4, 135.4, 134.0,
129.2, 128.8, 128.4, 128.15, 128.09, 124.9, 73.5, 69.3.
Benzyl Cyclohexyl Ether (26)
BnOSiMe3 (0.21 g, 1.15 mmol), cyclohexanone (0.1 ml, 1 mmol), and
Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the stock catalyst
solution prepared from FeCl3 (1 mL) was added, and the mixture was
stirred for 1 h. EtOAc (10 mL) was added, and the mixture was washed
with sat. aq NaHCO3 (2 × 3 mL). The aqueous phases were combined
and washed with EtOAc (3 mL), and then the organic phases were
combined and dried (Na2SO4). The crude product was purified by
flash chromatography (silica gel, gradient 0–35% EtOAc–hexane) to
give a colorless oil; yield: 162 mg (85%); Rf = 0.68 (EtOAc–hexane,
1:4); purity: 93%.
Benzyl 4-Methylbenzyl Ether (23)
BnOSiMe3 (0.18 g, 1 mmol), 4-methylbenzaldehyde (0.14 g, 1 mmol),
and Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the stock cata-
lyst solution (1 mL) was added, and the mixture was stirred for 1 h.
EtOAc (10 mL) was then added and the solution was washed with sat.
aq NaHCO3 (2 × 3 mL). The aqueous phases were combined and
washed with EtOAc (3 mL), and then the organic phases were com-
bined and dried (Na2SO4). The crude product was purified by flash
chromatography (silica gel, gradient 0–35% EtOAc–hexane) to give a
colorless oil; yield: 186 mg (89%); Rf = 0.76 (EtOAc–hexane, 1:4); puri-
ty: 95%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.39–7.35 (m, 4 H), 7.32–
7.29 (m, 1 H), 7.28–7.25 (m, 2 H), 7.19–7.17 (m, 2 H), 4.56 (s, 2 H),
4.52 (s, 2 H), 2.36 (s, 3 H).
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 139.1, 137.7, 135.9, 129.4,
128.7, 128.2, 128.1, 127.9, 72.5, 72.4, 21.3.
Alternatively, CyOSiMe3 (0.17 g, 1.0 mmol), PhCHO (0.1 mL, 1.0
mmol), and Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the
stock catalyst solution prepared from FeCl3 (1 mL) was added, and the
mixture was stirred for 30 min. EtOAc (10 mL) was added, and the
mixture was washed with sat. aq NaHCO3 (2 × 3 mL). The aqueous
phases were combined and washed with EtOAc (3 mL), and then the
organic phases were combined and dried (Na2SO4). The crude product
was purified by flash chromatography (silica gel, gradient 0–35%
EtOAc–hexane) to give a colorless oil; yield: 166 mg (87%); Rf = 0.68
(EtOAc–hexane, 1:4); purity: >99%.
1H NMR (600.13 MHz, CD2Cl2, 25 °C): δ = 7.36–7.32 (m, 4 H), 7.29–
7.25 (m, 1 H), 4.52 (s, 2 H), 3.39–3.35 (m, 1 H), 1.95–1.93 (br m, 2 H),
1.78–1.71 (m, 2 H), 1.55–1.53 (m, 1 H), 1.39–1.17 (m, 5 H).
13C NMR (150.92 MHz, CD2Cl2, 25 °C): δ = 140.1, 128.6, 127.8, 127.6,
69.9, 32.6, 26.3, 24.5.
3-[(Benzyloxy)methyl]phenol (24)
BnOSiMe3 (0.18 g, 1.0 mmol), 3-hydroxybenzaldehyde (0.12 g, 1.0
mmol), and Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the
stock catalyst solution (1 mL) was added, and the mixture was stirred
for 1 h. EtOAc (10 mL) was then added and the mixture was washed
with sat. aq NaHCO3 (2 × 3 mL). The aqueous phases were combined
and washed with EtOAc (3 mL), and then the organic phases were
combined and dried (Na2SO4). The crude product was purified by
flash chromatography (silica gel, gradient 0–80% EtOAc–hexane) to
give a colorless oil; yield: 178 mg (83%); Rf = 0.21 (EtOAc–hexane,
1:4); purity: >99%.
Cyclohexyl 4-Methylbenzyl Ether (27)
CyOSiMe3 (0.17 g, 1.0 mmol), 4-methylbenzaldehyde (0.12 mL, 1.0
mmol), and Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the
stock catalyst solution prepared from FeCl3 (1 mL) was added, and the
mixture was stirred for 30 min. EtOAc (10 mL) was added, and the
mixture was washed with sat. aq NaHCO3 (2 × 3 mL). The aqueous
phases were combined and washed with EtOAc (3 mL), and then the
organic phases were combined and dried (Na2SO4). The crude product
was purified by flash chromatography (silica gel, gradient 0–35%
EtOAc–hexane) to give a colorless oil; yield: 164 mg (80%); Rf = 0.77
(EtOAc–hexane, 1:4); purity: >99%.
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 7.39–7.29 (m, 5 H), 7.21 (t,
J = 7.9 Hz, 1 H), 6.92–6.90 (m, 1 H), 6.85–6.84 (m, 1 H), 6.75–6.73 (m,
1 H), 5.38 (br s, 1 H), 4.56 (s, 2 H), 4.52 (s, 2 H).
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Synthesis
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 7.23 (d, J = 7.8 Hz, 2 H), 7.15
(d, J = 7.8 Hz, 2 H), 4.48 (s, 2 H), 3.38–3.32 (m, 1 H), 2.34 (s, 3 H), 1.95–
1.92 (m, 2 H), 1.78–1.73 (m, 2 H), 1.56–1.52 (m, 1 H), 1.39–1.22 (m, 5
H).
13C NMR (125.76 MHz, CD2Cl2, 25 °C): δ = 137.3, 137.0, 129.2, 127.9,
77.2, 69.8, 32.7, 26.3, 24.5, 21.3.
13C NMR (125.76 MHz, CDCl3, 25 °C): δ = 77.6, 68.1, 32.5, 32.0, 30.4,
29.6, 29.4, 26.4, 26.0 24.4, 22.8, 14.2.
1,3-Dimethylbutyl Octyl Ether (31)
Octyloxy(trimethyl)silane (0.20 g, 1.0 mmol), i-BuCOMe (0.12 mL, 1.0
mmol), and Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the
stock catalyst solution prepared from FeCl3 (1 mL) was added, and the
mixture was stirred for 30 min. Hexane (10 mL) was then added and
the mixture was washed with sat. aq NaHCO3 (3 mL). The aqueous
phases were combined and washed with EtOAc (2 × 3 mL), and then
the organic phases were combined and dried (Na2SO4). The crude
product was purified by flash chromatography (silica gel, gradient 0–
35% EtOAc–hexane) to give a colorless oil; yield: 165 mg (77%); Rf =
0.89 (EtOAc–hexane, 1:9); purity: 99%.
Methyl 4-[(Cyclohexyloxy)methyl]benzoate (28)
CyOSiMe3 (0.17 g, 1.0 mmol), methyl 4-formylbenzoate (0.16 g, 1.0
mmol), and Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the
stock catalyst solution prepared from FeCl3 (1 mL) was added, and the
mixture was stirred for 30 min. EtOAc (10 mL) was added, and the
mixture was washed with sat. aq NaHCO3 (2 × 3 mL). The aqueous
phases were combined and washed with EtOAc (3 mL), and then the
organic phases were combined and dried (Na2SO4). The crude product
was purified by flash chromatography (silica gel, gradient 0–60%
EtOAc–hexane) to give a colorless oil; yield: 198 mg (80%); Rf = 0.67
(EtOAc–hexane, 1:4); purity: >99%.
1H NMR (500.13 MHz, CDCl3, 25 °C): δ = 3.35–3.47 (m, 1 H), 3.44–3.38
(m, 1 H), 3.31–3.26 (m, 1 H), 1.78–1.70 (m, 1 H), 1.57–1.45 (m, 3 H),
1.36–1.22 (m, 10 H), 1.17–1.10 (m, 4 H), 0.89–0.77 (m, 9 H).
13C NMR (125.76 MHz, CDCl3, 25 °C): δ = 73.6, 68.6, 46.5, 32.0, 30.4,
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 7.98 (ddd, J = 1.9, 8.4 Hz, 2
H), 7.42 (d, J = 8.4 Hz, 2 H), 4.58 (s, 2 H), 3.88 (s, 3 H), 3.39–3.34 (m, 1
H), 1.95–1.93 (br m, 2 H), 1.78–1.73 (m, 2 H), 1.56–1.51 (m, 1 H),
1.40–1.20 (m, 5 H).
13C NMR (125.76 MHz, CD2Cl2, 25 °C): δ = 167.2, 145.5, 129.8, 129.5,
127.4, 77.7, 69.4, 52.3, 32.6, 26.2, 24.4.
29.6, 29.4, 26.4, 24.8, 23.2, 22.8, 22.7, 20.1, 14.2.
Benzyl (–)-Menthyl Ether (32)
(–)-Menthyl trimethylsilyl ether (0.23 g, 1.0 mmol), PhCHO (0.1 mL,
1.0 mmol), and Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the
stock catalyst solution prepared from FeCl3 (1 mL) was added, and the
mixture was stirred for 30 min. EtOAc (10 mL) was added, and the
mixture was washed with sat. aq NaHCO3 (2 × 3 mL). The aqueous
phases were combined and washed with EtOAc (3 mL), and then the
organic phases were combined and dried (Na2SO4). The crude product
was purified by flash chromatography (silica gel, gradient 0–35%
EtOAc–hexane) to give a colorless oil; yield: 217 mg (88%); Rf = 0.78
(EtOAc–hexane, 1:4); purity: >99%; dr 100:0 (1R,2S,4R/1S,2S,4R).
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 7.38–7.32 (m, 4 H), 7.29–
7.25 (m, 1 H), 4.65 (d, J = 11.6 Hz, 1 H), 4.38 (d, J = 11.6 Hz, 1 H), 3.19
(ddd, J = 4.1, 10.5 Hz, 1 H), 2.34–2.25 (m, 1 H), 2.25–2.20 (m, 1 H),
1.70–1.62 (m, 2 H), 1.44–1.34 (m, 1 H), 1.31–1.25 (m, 1 H), 1.05–0.84
(m, 9 H), 0.75 (d, J = 6.9 Hz, 3 H).
Biphenyl-4-ylmethyl Cyclohexyl Ether (29)
CyOSiMe3 (0.17 g, 1.0 mmol), biphenyl-4-carboxaldehyde (0.18 g, 1.0
mmol), and Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the
stock catalyst solution prepared from FeCl3 (1 mL) was added, and the
mixture was stirred for 30 min. EtOAc (10 mL) was added, and the
mixture was washed with sat. aq NaHCO3 (2 × 3 mL). The aqueous
phases were combined and washed with EtOAc (3 mL), and then the
organic phases were combined and dried (Na2SO4). The crude product
was purified by flash chromatography (silica gel, gradient 0–35%
EtOAc–hexane) to give a colorless oil; yield: 225 mg (85%); Rf = 0.61
(EtOAc–hexane, 1:4); purity: >99%.
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 7.64–7.58 (m, 4 H), 7.47–
7.42 (m, 4 H), 7.36 (tt, J = 1.5, 7.3 Hz, 1 H), 4.58 (s, 2 H), 3.43–3.38 (m,
1 H), 1.99–1.96 (m, 2 H), 1.81–1.75 (m, 2 H), 1.58–1.53 (m, 1 H), 1.43–
1.23 (m, 5 H).
13C NMR (125.76 MHz, CD2Cl2, 25 °C): δ = 141.3, 140.4, 139.2, 129.2,
128.3, 127.6, 127.4, 127.3, 77.4, 69.7, 32.7, 26.3, 24.5.
13C NMR (125.76 MHz, CD2Cl2, 25 °C): δ = 140.0, 128.6, 128.2, 127.6,
79.2, 70.6, 48.9, 40.7 35.0, 32.0, 26.0, 23.7, 22.6, 21.2, 16.3.
Biphenyl-4-ylmethyl (–)-Menthyl Ether (33)
(–)-Menthyl trimethylsilyl ether (0.23 g, 1.0 mmol), biphenyl-4-car-
boxaldehyde (0.18 g, 1.0 mmol), and Et3SiH (0.17 mL, 1.05 mmol)
were mixed together, the stock catalyst solution prepared from FeCl3
(1 mL) was added, and the mixture was stirred for 30 min. EtOAc (10
mL) was added, and the mixture was washed with sat. aq NaHCO3 (2 ×
3 mL). The aqueous phases were combined and washed with EtOAc (3
mL), and then the organic phases were combined and dried (Na2SO4).
The crude product was purified twice by flash chromatography (silica
gel, gradient 0–35% EtOAc–hexane then gradient 0–10% EtOAc–
hexane) to give a colorless oil; yield: 245 mg (76%); Rf = 0.69 (EtOAc–
hexane, 1:4); purity: >99%; dr 100:0 (1R,2S,4R/1S,2S,4R).
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 7.64–7.59 (m, 4 H), 7.48–
7.43 (m, 3 H), 7.36 (tt, J = 1.3, 7.3 Hz, 1 H), 4.71 (d, J = 11.5 Hz, 1 H)
4.43 (d, J = 11.5 Hz, 1 H), 3.23 (ddd, J = 4.1, 10.5 Hz, 1 H), 2.38–2.29 (m,
1 H), 2.28–2.24 (m, 1 H), 1.72–1.64 (m, 2 H), 1.47–1.36 (m, 1 H), 1.34–
1.28 (m, 1 H), 1.08–0.89 (m, 9 H), 0.78 (d, J = 8.2 Hz, 3 H).
Cyclohexyl Octyl Ether (30)
Octyloxy(trimethyl)silane (0.20 g, 1.0 mmol), cyclohexanone (0.12
mL, 1.0 mmol), and Et3SiH (0.17 mL, 1.05 mmol) were mixed together,
the stock catalyst solution prepared from FeCl3 (1 mL) was added, and
the mixture was stirred for 30 min. EtOAc (10 mL) was added, and the
mixture was washed with sat. aq NaHCO3 (3 mL). The aqueous phases
were combined and washed with EtOAc (2 × 3 mL), and then the or-
ganic phases were combined and dried (Na2SO4). The crude product
was purified by flash chromatography (silica gel, gradient 0–35%
EtOAc–hexane) to give a colorless oil; yield: 191 mg (90%); Rf = 0.81
(EtOAc–hexane, 1:4); purity: 99%.
1H NMR (500.13 MHz, CDCl3, 25 °C): δ = 3.42 (t, J = 6.8 Hz, 2 H), 3.21–
3.16 (m, 1 H), 1.92–1.88 (br m, 2 H), 1.74–1.70 (br m, 2 H), 1.59–1.50
(m, 3 H), 1.33–1.16 (m, 15 H), 0.87 (t, J = 6.9 Hz, 3 H).
13C NMR (125.76 MHz, CD2Cl2, 25 °C): δ = 141.3, 140.5, 139.1, 129.2,
128.6, 127.6, 127.4, 127.3, 79.3, 70.3, 48.9, 40.8, 35.1, 32.0, 26.1, 23.8,
22.6, 21.2, 16.4.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1749–1760

1758
R. Savela, R. Leino
Paper
Synthesis
Allyl Benzyl Ether (34)
Acknowledgment
AllOSiMe3 (0.17 mL, 1.0 mmol), PhCHO (0.10 mL, 1.0 mmol), and
Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the stock catalyst
solution prepared from FeCl3 (1 mL) was added, and the mixture was
stirred for 30 min. Hexane (10 mL) was then added and the mixture
was washed with sat. aq NaHCO3 (2 × 3 mL). The aqueous phases were
combined and washed with hexane (3 mL), and then the organic
phases were combined and dried (Na2SO4). The crude product was
purified by flash chromatography (silica gel, gradient 0–35% EtOAc–
hexane) to give a colorless oil; yield: 119 mg (80%); Rf = 0.68 (EtOAc–
hexane, 1:4); purity: 96%.
Financial support to R.S. from the National Doctoral Program of Or-
ganic Chemistry and Chemical Biology (2010–2013), Stiftelsen för
Åbo Akademi, Kemian päivien säätiö, Orion Farmos Research Founda-
tion, and Magnus Ehrnrooth Foundation is gratefully acknowledged.
We also thank Johan Lindén for assistance with Mössbauer spectros-
copy.
Supporting Information
1H NMR (500.13 MHz, CD2Cl2, 25 °C): δ = 7.38–7.34 (m, 4 H), 7.32–
7.28 (m, 1 H), 6.01–5.94 (m, 1 H), 5.32 (qd, J = 1.7, 17.2 Hz, 1 H) 5.22–
5.19 (m, 1 H), 4.52 (s, 2 H), 4.04 (td, J = 1.5, 5.5 Hz, 2 H).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380155. Included are details on
catalyst preparation and characterization and copies of NMR and GC
13C NMR (125.76 MHz, CD2Cl2, 25 °C): δ = 139.1, 135.5, 128.7, 128.0,
chromatograms of the isolated products.
S
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127.9, 116.8, 72.5, 71.5.
References
Allyl 4-Fluorobenzyl Ether (35)
AllOSiMe3 (0.17 mL, 1.0 mmol), 4-FC6H4CHO (0.11 mL, 1.0 mmol), and
Et3SiH (0.17 mL, 1.05 mmol) were mixed together, the stock catalyst
solution prepared from FeCl3 (1 mL) was added, and the mixture was
stirred for 30 min. Hexane (10 mL) was then added and the mixture
was washed with sat. aq NaHCO3 (2 × 3 mL). The aqueous phases were
combined and washed with hexane (3 mL), and then the organic
phases were combined and dried (Na2SO4). The crude product was
purified by flash chromatography (silica gel, gradient 0–35% EtOAc–
hexane) to give a colorless oil; yield: 152 mg (92%); Rf = 0.63 (EtOAc–
hexane, 1:4); purity: 95%.
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2-Adamantyl Allyl Ether (36)
AllOSiMe3 (0.17 mL, 1.0 mmol), adamantan-2-one (0.15 g, 1.0 mmol),
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hexane) to give a colorless oil; yield: 139 mg (72%); Rf = 0.77 (EtOAc–
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1H NMR (500.13 MHz, CDCl3, 25 °C): δ = 5.97–5.92 (m, 1 H), 5.28 (qd,
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36.7, 31.9, 31.7, 27.6.
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R. Savela, R. Leino
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1749–1760

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1749–1760