One-pot sequential synthesis of ethers from an aliphatic carboxylic acid and an alcohol by indium-catalyzed deoxygenation of an ester

Article abstract of DOI:10.1002/ejoc.201200552

We have developed a widely applicable and direct method of etherification from a carboxylic acid and an alcohol by indium-catalyzed deoxygenation of the transient ester formed in a one-pot reaction. This simple catalytic reducing system appears to be remarkably tolerant of several functional groups including alkenes, halogens, nitro and heterocyclic groups. A reducing system composed of InBr₃ and an economical hydrosiloxane, PMHS (polymethylhydrosiloxane) , enabled one-pot etherification by using a variety of aliphatic carboxylic acids and alcohols. Copyright

Full text of DOI:10.1002/ejoc.201200552

Job/Unit: O20552
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FULL PAPER
DOI: 10.1002/ejoc.201200552
One-Pot Sequential Synthesis of Ethers from an Aliphatic Carboxylic Acid and
an Alcohol by Indium-Catalyzed Deoxygenation of an Ester
Norio Sakai,*[a] Yuta Usui,[a] Toshimitsu Moriya,[a] Reiko Ikeda,[a] and Takeo Konakahara[a]
Keywords: Indium / Reduction / Silanes / Ethers / Esters
We have developed a widely applicable and direct method
of etherification from a carboxylic acid and an alcohol by in-
dium-catalyzed deoxygenation of the transient ester formed
in a one-pot reaction. This simple catalytic reducing system
appears to be remarkably tolerant of several functional
groups including alkenes, halogens, nitro and heterocyclic
groups.
with an RhCl(cod)2/Ph2SiH2 reducing system led to the
production of the corresponding diol.[8] In this context, the
recent synthesis of esters or ethers from carboxylic acids or
alcohols with dialkyl dicarbonates in the presence of
Mg(ClO4)2 has been reported by several groups.[9] From an
atom economy perspective these methods waste 1 equiv. of
the alkyl alcohol with liberation of CO2. As far as we know,
there is no reported example of a one-pot synthesis of ether
derivatives by an equimolar condensation of a carboxylic
acid and an alcohol without dehydration or the use of ex-
cess amounts of condensing substrates.[10,11]
With these precedents in mind, and as a further exten-
sion of conventional chemoselective transformation using
an indium catalyst and a hydrosilane,[12,13] we envisioned
the development of a simple and direct etherification of
carboxylic acids and alcohols by indium-catalyzed deoxy-
genation of a transient ester. Herein we report the details.
Introduction
The synthesis of ethers has a fundamentally important
and central position in organic and materials chemistry, and
a number of approaches have been developed for their prac-
tical preparation. Typical methods include the reaction of
an alkoxy anion with an alkyl halide/sulfonate under
strongly basic conditions (Williamson ether synthesis), and
the acid-promoted dehydrogenating condensation of
alcohols.[1] Since the 1960s, the preparation of ethers has
typically been accomplished by a direct reduction of the
carbonyl function of esters and thio esters through treat-
ment with reducing agents, such as LiAlH4,[2] DIBAL,[3]
and organotin hydride.[4] Recently, several groups have re-
ported that the combination of a metal catalyst or metal
complex, such as Ni, Ti, Mn, Ru and B, and a milder reduc-
ing reagent with a hydrosilane, either directly or stepwise,
will result in the deoxygenation of the carbonyl function
of esters to render the corresponding ether.[5,6] A reductive
coupling of carbonyl compounds to ethers has also been
achieved by using several Lewis acids and hydrosilanes.[7]
However, a typical Williamson ether synthesis requires
strongly basic conditions that cause undesired side reac-
tions such as elimination of the alkylating agent that reduce
both selectivity and yield. Selective reduction of esters with
hydrosilanes to afford the corresponding ethers was barely
accomplished by relatively expensive and/or complicated
manganese and ruthenium complexes.[5b,5d] A Cp2TiF2-
PMHS (polymethylhydrosiloxane) reducing system that has
been shown effective at converting lactones to cyclic ethers,
also requires a complicated two-step procedure.[6a] Ad-
ditionally, it has been shown that reduction of a lactone
Results and Discussion
In a preliminary study, we initially found that when the
reaction of 3-phenylpropionic acid with 1 equiv. of phen-
ethyl alcohol was treated with 5 mol-% of InBr3 [or
In(OTf)3] in PhMe at 110 °C, 2-phenylethyl benzylacetate
was obtained in a 93% (or 95%) yield (Scheme 1). This pro-
cedure did not require azeotropic removal or the combined
use of excessive amounts of alcohol and dehydrating agents.
Therefore, we attempted to show that further addition of a
silane to the resultant mixture containing InBr3 would eas-
ily produce the corresponding unsymmetrical ether in a
one-pot reaction (Table 1). As expected, when the reaction
was carried out with 4 equiv. of Et3SiH, the desired unsym-
metrical ether was obtained in 60% yield (Table 1, Entry 1),
and the indium salt remained intact during the total reac-
tion. When the reduction was then carried out with a
stronger reducing hydrosilane, PhSiH3, and a weaker reduc-
ing agent, TMDS (tetramethyldisiloxane), each yield was
[a] Department of Pure and Applied Chemistry, Faculty of Science
and Technology, Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
Fax: +81-4-7123-9890
E-mail: sakachem@rs.noda.tus.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200552.
Eur. J. Org. Chem. 0000, 0–0
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N. Sakai, Y. Usui, T. Moriya, R. Ikeda, T. Konakahara
FULL PAPER
slightly improved (Table 1, Entries 2 and 3).[14] When the ing a nitro group with phenethyl alcohol proceeded
reaction was run with a weaker hydrosiloxane, PMHS, the smoothly, the rate of the second reduction was rather low
yield dramatically improved to 92% (Table 1, Entry 4). Al- (Table 2, Entry 5). We hypothesize that the nitro group
though the reaction mixture became a solid gel during the probably retards activation of the carbonyl group by the
reaction by using an excess amount of PMHS (10 equiv.), indium catalyst. When this reaction was run by using an
the expected reduction proceeded with continuous heating acid substrate with a naphthyl ring, the result was excellent
to produce the ether.[15] The reducing strength of the silane (Table 2, Entry 6). When the reaction of a typical dicar-
played an important role in promoting etherification. In ad- boxylic acid, glutaric acid, was conducted with 2 equiv. of
dition, the key to this reaction was the reaction temperature alcohol, the corresponding ether 8 was obtained in a 58%
at the esterification step. For example, when a similar reac- yield (Table 2, Entry 7). In addition, when using an acid
tion consisting of InBr3 and PMHS was conducted at with a pendant heterocyclic ring, such as thiophene, a slight
80 °C, the product yield was moderate with recovery (21%) decrease in the yield was observed, though the desired ether
of the carboxylic acid (Table 1, Entry 5). Also, the addition 9 was obtained along with a 37% yield of the intermediate
of both sulfuric acid (0.1 equiv.) as a dehydrating agent and ester (Table 2, Entry 8). In contrast, although esterification
slightly more alcohol (1.2 equiv.) markedly promoted the
initial esterification, resulting in production of the ether
in excellent yield (Table 1, Entry 6). Refluxing in
CH2ClCH2Cl resulted in a similar effect.
Table 2. One-pot synthesis of ethers from various carboxylic acids
and phenethyl alcohol.
Scheme 1. Indium-catalyzed esterification.
Table 1. Examination of reaction conditions.
Entry
Conditions A[a]
Solvent Temp. Time
Conditions B
Silane
Temp.
[°C]
Yield
[%][b]
[°C]
[h]
1
2
3
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DCE[f]
110
110
110
110
80
110
80
20
20
20
20
20
4
Et3SiH[d]
TMDS[d]
PhSiH3
PMHS
PMHS
PMHS
PMHS
110
110
110
110
80
110
80
60
(75)[c]
(72)[c]
92
[d]
4
5
(60)[c]
92
6[e]
7[e]
4
86
[a] Reaction conditions: InBr3 (0.030 mmol), carboxylic acid
(0.60 mmol), alcohol (0.60–0.72 mmol), solvent (0.60 mL). [b] Iso-
lated yield. [c] NMR yield. [d] 4 equiv. (Si-H). [e] Sulfuric acid
(0.10 equiv.) and alcohol (1.2 equiv.) were used. [f] DCE = 1,2-
dichloroethane.
Under the optimized conditions shown in Table 1, the
generality of this etherification was examined by using a
variety of carboxylic acids and phenethyl alcohol as the
alcohol of choice (Table 2). In most cases, the initial esterifi-
cation and subsequent etherification proceeded cleanly, pro-
ducing the corresponding ether derivatives in moderate to
good yields. Because a halogen substituent, such as a chlor-
ide, bromide or an iodide substituent, on the benzene ring
is tolerant of this reduction system, selective deoxygenation
of the transiently formed ester was observed (Table 2, En-
[a] Isolated yield. [b] Solvent = DCE. [c] Recovery of the ester after
the second step is shown in parentheses. [d] Alcohol (1.2 equiv.).
[e] Alcohol (2 equiv.). [f] Yield of the corresponding ester at the first
tries 2–4). Although esterification of a carbocyclic acid hav- step is shown in parentheses.
2
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Ethers from an Aliphatic Carboxylic Acid and an Alcohol
of a substrate acid bearing a thioether moiety with phen- a 52% yield (Table 3, Entry 3). These results implied that,
ethyl alcohol gave the corresponding ester in 80%, the sec- unlike the cases with phenethyl alcohol, the efficiency of
ond reduction did not occur cleanly, leading to the forma- initial esterification is subject to the alcohol sterics. Ad-
tion of a complex mixture (Table 2, Entry 9). These results ditionally, it was found that terminal alkenes on the alcohol
suggest that the indium catalyst strongly coordinates to the fragment appear to be tolerant of the present reducing
softer sulfur atom rather than the harder carbonyl oxygen agents as reflected by production of ether 16 in good yield
atom of the ester group, thus complicating the reaction (Table 3, Entry 4). Unfortunately, with allyl alcohol and
path. The use of a branched cyclohexanecarboxylic acid phenol, the expected ethers were obtained in only 40 and
gave the unsymmetrical ether 11 in 71% (Table 2, Entry 10). 28% yields, respectively; in each case low yields of etherifi-
In the case of a substrate having a sterically more de- cation correlate to low esterification yields attributable most
manding substituent generation of the desired ether was likely to the low nucleophilicity of both alcohols (Table 3,
again attenuated (Table 2, Entry 11). The observed recovery Entries 5 and 7).[16] On the other hand, when the etherifi-
of the ester in this case suggests the susceptibility of the cation was conducted with benzyl alcohol, the di-
second reduction event to the effects of steric demands. Un- phenylmethane derivative 18Ј, which was formed through a
fortunately, the reducing system by using InBr3 and a series substitution reaction between the alcohol and the solvent
of silanes could not be applied to the reduction of esters in the first step, was obtained as a major product (Table 3,
derived from benzoic acid.[13h]
Entry 6). This result is in agreement with our previous re-
The breadth of application of the present etherification sults, in which an InBr3/PhSiH3 reducing system directly
was investigated with other alcohols, and the results are produced diphenylmethane derivatives from aromatic car-
summarized in Table 3. Because the use of a secondary boxylic acids and electron-rich aromatic compounds.[13c]
alcohol led to a decrease in initial esterification, the effect These data were also consistent with experiments in which
of sulfuric acid as a dehydrating reagent in such reactions an InCl3·4H2O-catalyzed dehydration of electron-rich aro-
was examined. For example, when the reaction with either matic compounds with benzyl alcohols afforded diaryl-
2-butanol or cyclohexanol was performed with 0.1 equiv. methanes.[17]
of sulfuric acid, the corresponding ethers 13 and 14 were
A plausible mechanism for the indium-catalyzed re-
obtained in moderate to good yields (Table 3, Entries 1 and ductive deoxygenation of esters en route to ethers is shown
2). Etherification by using both a carboxylic acid with a in Scheme 2. We envision that InBr3 has several roles, the
branched skeleton and a secondary alcohol gave ether 15 in first being to promote the condensation of a carboxylic acid
and an alcohol and to subsequently activate the ester
formed in situ to facilitate hydrosilylation by a silane.[13a]
The silyl acetal thus generated is then again activated by
and alcohols.
Table 3. One-pot synthesis of ethers from various carboxylic acids
InBr3, transforming the corresponding ether by the second
hydrosilylation and desiloxylation.[18,19] Generation of the
silyl acetal from the corresponding ester was examined by
NMR spectroscopy; no acetal intermediate, except for the
final ether product, could be observed. In addition, because
the iodine substituent on the benzene ring remained intact
throughout the reduction, we hypothesize that the present
reduction proceeds through an ionic mechanism rather than
a radical process.[13g]
Scheme 2. Plausible pathway for the preparation of an ether.
Conclusions
We have demonstrated direct etherification from a vari-
ety of aliphatic carboxylic acids and alcohols using a reduc-
ing system composed of InBr3 and PMHS in a one-pot pro-
cedure. This simple catalytic system appears to be remarka-
bly tolerant of several functional groups involving alkenes,
[a] Isolated yield. [b] Sulfuric acid (0.1 equiv.). [c] Alcohol
(1.2 equiv.). [d] Yield of a mixture of o,p-diphenylmethane deriva-
tives 18Ј at the first step is shown in parentheses.
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N. Sakai, Y. Usui, T. Moriya, R. Ikeda, T. Konakahara
FULL PAPER
[M + Na]+. HRMS (ESI): calcd. for C18H22O [M + Na]+ 277.1568;
found 277.1580.
halogens, the nitro group, and heterocycles. In addition, un-
like the Williamson ether synthesis that uses a strong base,
this procedure proceeds cleanly under relatively gentle con-
2-(4-Chlorophenyl)ethyl 2-Phenylethyl Ether (3): 142 mg (91%); a
1
ditions thus, extending the scope of possible substrates and colorless liquid. H NMR (300 MHz, CDCl3): δ = 2.80–2.88 (m, 4
H, -CH2-), 3.59–3.66 (m, 4 H, -CH2-O), 7.09 (d, J = 8.7 Hz, 2 H,
Ar-H), 7.17–7.27 (m, 7 H, Ar-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 35.5, 36.2, 71.4, 71.8, 126.1, 128.2, 128.3, 128.8, 130.2,
131.8, 137.6, 138.9 ppm. MS (ESI): m/z (%) = 283 (100) [M +
Na]+. HRMS (FAB): calcd. for C16H18ClO 261.1046; found
261.1046.
providing a simpler and more convenient alternative to
traditional etherification methods.
Experimental Section
General: All reactions were carried out under N2, unless otherwise
noted. Dichloroethane (CH2ClCH2Cl) and chloroform (CHCl3)
were first distilled from P2O5, and the distillates were distilled again
from K2CO3 prior to use. Toluene was distilled from sodium and
benzophenone. All indium catalysts were commercially available
and were basically used without further purification. When an in-
dium compound was hygroscopic, the powder was heated at 140 °C
under vacuum for 1 h. All carboxylic acids were commercially
available and were used without purification. Silanes were used
without further purification. Reactions were monitored by thin-
layer chromatography (TLC) or gas chromatography (GC) of reac-
tion aliquots. TLC was performed by using silica gel 60 F254 plates,
and reaction components were visualized with UV light. Column
2-(4-Bromophenyl)ethyl 2-Phenylethyl Ether (4): 165 mg (90%); a
colorless liquid. 1H NMR (500 MHz, CDCl3): δ = 2.80 (t, J =
7.0 Hz, 2 H, -CH2-), 2.85 (t, J = 7.0 Hz, 2 H, -CH2-), 3.59–3.64
(m, 4 H, -CH2-O), 7.03 (d, J = 8.5 Hz, 2 H, Ar-H), 7.16–7.21 (m,
3 H, Ar-H), 7.23–7.28 (m, 2 H, Ar-H), 7.36 (t, J = 8.5 Hz, 2 H,
Ar-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 35.6, 36.2, 71.3,
71.8, 119.9, 126.1, 128.2, 128.8, 130.6, 131.3, 138.1, 138.9 ppm. MS
(ESI): m/z (%) = 327 (100) [M + Na]+. HRMS (FAB): calcd. for
C16H18BrO 305.0541; found 305.0546.
2-(2-Iodophenyl)ethyl 2-Phenylethyl Ether (5): 180 mg (85%); an
orange liquid. 1H NMR (300 MHz, CDCl3): δ = 2.88 (t, J = 7.2 Hz,
2 H, -CH2-), 3.00 (t, J = 7.2 Hz, 2 H, -CH2-), 3.61–3.69 (m, 4 H,
-CH2-O), 6.88 (m, 1 H, Ar-H), 7.19–7.25 (m, 7 H, Ar-H), 7.78 (d,
J = 7.8 Hz, 2 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
36.2, 40.9, 70.0, 71.8, 100.7, 126.1, 128.0, 128.2 (2 C), 128.9, 130.2,
138.9, 139.3, 141.4 ppm. MS (FAB): m/z (%) = 353 (100) [M +
Na]+. HRMS (FAB): calcd. for C16H18IO 353.0402; found
353.0398.
1
chromatography was also performed by using silica gel. H NMR
spectra were measured at 500 (or 300) MHz by using tetramethylsil-
ane as an internal standard. 13C NMR spectra were measured at
125 (or 75) MHz by using the center peak of chloroform (δ
=77.0 ppm) as an internal standard. High-resolution mass spectra
(HRMS) were measured by using NBA (3-nitrobenzylalcohol) as a
matrix with a JEOL JMS-700 MStation.
2-(4-Nitrophenyl)ethyl 2-Phenylethyl Ether (6): 37 mg (23%); a col-
orless liquid. 1H NMR (500 MHz, CDCl3): δ = 2.85 (t, J = 6.5 Hz,
2 H, -CH2-), 2.94 (t, J = 6.5 Hz, 2 H, -CH2-), 3.64 (t, J = 6.5 Hz,
2 H, -CH2-O), 3.67 (t, J = 6.5 Hz, 2 H, -CH2-O), 7.15–7.31 (m, 7 H,
Ar-H), 8.09 (d, J = 8.5 Hz, 2 H, Ar-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 36.1, 36.2, 70.6, 71.9, 123.4, 126.2, 128.3, 128.8, 129.7,
138.9, 147.3 ppm. MS (ESI): m/z (%) = 294 (100) [M + Na]+.
HRMS (ESI): calcd. for C16H17NO3 [M + Na]+ 294.1106; found
294.1103.
General Procedure for the One-Pot Synthesis of Ethers: Tables 2 and
3. To a 10 mL screw-capped vial or a 10 mL flask containing
freshly distilled PhMe (0.60 mL), under N2, a carboxylic acid
(0.60 mmol), an alcohol (0.60 mmol) and InBr3 (11 mg,
0.030 mmol) [or 98% H2SO4 (6.0 mg, 0.060 mmol)] were added in
succession. The resultant mixture was stirred at 110 °C (bath tem-
perature), and monitored by TLC for 20 h. Polymethylhydrosilox-
ane (6.0–12.0 mmol) was added to the resultant mixture by using
a syringe, and the mixture was further heated at 110 °C for 4–8 h.
The solution turned to a gel 30–60 min after the beginning of the
second heating. After the reaction, the resulting gel was cooled to
room temp. To extract the product, the gel was washed with AcOEt
(5 mL ϫ5), and the combined organic solutions were then concen-
trated under reduced pressure. The crude product was purified by
silica gel column chromatography (Hex/AcOEt) to afford the corre-
sponding ether.
2-(1-Naphthyl)ethyl 2-Phenylethyl Ether (7): 153 mg (92%); a yel-
1
low liquid. H NMR (500 MHz, CDCl3): δ = 2.88 (t, J = 7.5 Hz,
2 H, -CH2-), 3.35 (t, J = 7.5 Hz, 2 H, -CH2-), 3.67 (t, J = 7.5 Hz,
2 H, -CH2-O), 3.77 (t, J = 7.5 Hz, 2 H, -CH2-O), 7.18–7.39 (m, 7
H, Ar-H), 7.44–7.51 (m, 2 H, Ar-H), 7.71 (d, J = 8.0 Hz, 1 H, Ar-
H), 7.83 (d, J = 8.0 Hz, 1 H, Ar-H), 8.03 (d, J = 8.0 Hz, 1 H, Ar-
H) ppm. 13C NMR (125 MHz CDCl3): δ = 33.3, 36.3, 71.2, 71.9,
123.7, 125.4, 125.5, 125.8, 126.1, 126.8, 126.9, 128.3, 128.7, 128.9,
132.0, 133.8, 134.8, 138.9 ppm. MS (FAB): m/z (%) = 276 (100)
[M]+. HRMS (FAB): calcd. for C20H20O 276.1514; found 276.1515.
3-Phenylpropyl 2-Phenylethyl Ether (1):[20] 133 mg (92%); a color-
less liquid. 1H NMR (500 MHz, CDCl3): δ = 1.87 (quint, J =
7.5 Hz, 2 H, -CH2-), 2.65 (t, J = 7.5 Hz, 2 H, -CH2-), 2.88 (t, J =
7.5 Hz, 2 H, -CH2-), 3.42 (t, J = 7.5 Hz, 2 H, -CH2-O), 3.61 (t, J =
7.5 Hz, 2 H, -CH2-O), 7.12–7.29 (m, 10 H, Ar-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 31.2, 32.2, 36.3, 69.8, 71.7, 125.6, 126.1,
128.2, 128.4, 128.9, 139.1, 141.9 ppm. MS (EI): m/z (%) = 239 (100)
[M – H]–. HRMS (FAB): calcd. for C17H20O [M + H]+ 241.1592;
found 241.1588.
1,5-Bis[(2-phenylethyl)oxy]pentane (8): 109 mg (58%); a colorless li-
1
quid. H NMR (500 MHz, CDCl3): δ = 1.33–1.39 (m, 1 H, -CH2-
), 1.54–1.60 (m, 2 H, -CH2-), 2.88 (t, J = 7.5 Hz, 2 H, -CH2-), 3.42
(t, J = 7.5 Hz, 2 H, -CH2-O), 3.61 (t, J = 7.5 Hz, 2 H, -CH2-O),
7.18–7.29 (m, 5 H, Ar-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
22.7, 29.4, 36.3, 70.8, 71.7, 126.1, 128.2, 128.8, 139.0 ppm. MS
(ESI): m/z (%) = 335 (100) [M + Na]+. HRMS (ESI): calcd. for
C21H28O2 [M + Na]+ 335.1987; found 335.1975.
4-Phenylbutyl 2-Phenylethyl Ether (2): 125 mg (82%); a colorless
liquid. 1H NMR (500 MHz, CDCl3): δ = 1.61–1.66 (m, 4 H, 2-Phenylethyl 2-Thiophenylethyl Ether (9): 67 mg (48%); a yellow
1
-CH2-), 2.61 (t, J = 7.5 Hz, 2 H, -CH2-), 2.87 (t, J = 7.0 Hz, 2 H, liquid. H NMR (300 MHz, CDCl3): δ = 2.90 (t, J = 6.9 Hz, 2 H,
-CH2-), 3.44 (t, J = 6.5 Hz, 2 H, -CH2-O), 3.61 (t, J = 7.5 Hz, 2 -CH2-), 3.08 (t, J = 6.9 Hz, 2 H, -CH2-Ph), 3.67 (t, J = 6.9 Hz, 4
H, -CH2-O), 7.15–7.29 (m, 10 H, Ar-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 27.9, 29.3, 35.6, 36.3, 70.7, 71.8, 125.6. 126.1, 128.2 (2
C), 128.3, 128.8, 139.0, 142.4 ppm. MS (ESI): m/z (%) = 277 (100)
H, -CH2-O), 6.80 (d, J = 3.3 Hz, 1 H, thiophene-H), 6.90–6.93 (m,
1 H, thiophene-H), 7.12 (d, J = 5.1 Hz, 1 H, thiophene-H), 7.20–
7.30 (m, 5 H, Ph-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 30.4,
4
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Ethers from an Aliphatic Carboxylic Acid and an Alcohol
36.2, 71.4, 71.9, 123.5, 125.0, 126.1, 126.6, 128.3, 128.9, 138.9,
141.2 ppm. MS (ESI): m/z (%) = 255 (100) [M + Na]+. HRMS
(ESI): calcd. for C14H16OS [M + Na]+ 255.0819; found 255.0804.
3.38–3.41 (m, 4 H, -CH2-O), 4.93 (d, J = 10 Hz, 2 H, CH2=CH-),
5.00 (d, J = 17.5 Hz, 2 H, CH2=CH-), 5.81 (dd, J = 17.5, 10 Hz, 2
H, CH2=CH-), 7.15–7.28 (m, 5 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 26.0, 28.8, 28.9, 29.7, 31.3, 32.3, 33.7, 69.8, 70.9, 114.1,
125.6, 128.2, 128.4, 139.0, 142.0 ppm. MS (ESI): m/z (%) = 269
(100) [M + Na]+. HRMS (ESI): calcd. for C17H26O [M + Na]+
269.1881; found 269.1879.
Allyl 3-Phenylpropyl Ether (17): 42 mg (40%); a colorless liquid. 1H
NMR (500 MHz, CDCl3): δ = 1.90–1.94 (m, 2 H, -CH2-), 2.70 (t,
J = 7.5 Hz, 2 H, -CH2-), 3.44 (t, J = 6.5 Hz, 2 H, -CH2-O), 3.96
(d, J = 6.5 Hz, 2 H, O-CH2-CH=CH2), 5.17 (d, J = 10.5 Hz, 1 H,
CH2=CH-), 5.27 (d, J = 15.5 Hz, 1 H, CH2=CH-), 5.89–5.97 (dd,
J = 15.5, 10.5 Hz, 1 H, CH2=CH-), 7.16–7.29 (m, 5 H, Ar-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 31.3, 32.3, 69.4, 71.8, 116.7,
125.7, 128.2, 128.4, 135.0, 141.9 ppm. MS (ESI): m/z (%) = 199
(100) [M + Na]+. HRMS (ESI): calcd. for C12H16O [M + Na]+
199.1098; found 199.1097.
2- and 4-Benzyltoluene (18Ј):[13c] 93 mg (85%); a colorless oil. 1H
NMR (500 MHz, CDCl3): δ = 2.23 (s, 3 H, o-CH3), 2.30 (s, 3 H,
p-CH3), 3.93 (s, 2 H, p-CH2), 3.98 (s, 2 H, o-CH2), 7.06–7.28 (m,
9 H, o- and p-ArH) ppm. 13C NMR (125 MHz, CDCl3): δ = 19.6,
21.0, 39.4, 41.5, 125.9, 126.0, 126.4, 128.4, 128.4, 128.7, 128.80,
128.85, 128.90, 129.1, 129.9, 130.3, 135.5, 136.6, 138.1, 138.9,
140.4, 141.4 ppm. MS (FAB): m/z = 181 [M – H]. HRMS (FAB):
calcd. for C14H13 [M – H] 181.1017; found 181.1033.
Phenyl 3-Phenylpropyl Ether (19):[22] 36 mg (28%); a colorless li-
quid. 1H NMR (300 MHz, CDCl3): δ = 2.14–2.22 (m, 2 H,
-CH2-), 2.90 (t, J = 7.5 Hz, 2 H, -CH2-), 4.03 (t, J = 6.5 Hz, 2 H,
-CH2-O), 6.94–7.04 (m, 3 H, Ar-H), 7.24–7.40 (m, 7 H, Ar-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 31.1, 32.4, 66.9, 114.5, 120.5,
125.8, 128.3, 128.4, 129.3, 141.4, 158.8 ppm. MS (EI): m/z (%) =
212 (100) [M]+. HRMS (EI): Calcd for C15H16O [M + Na]+:
212.1201; found 212.1206.
2-Phenethyl 2-(Phenylthio)ethyl Ether (10): 131 mg (80%); a color-
1
less liquid. H NMR (500 MHz, CDCl3): δ = 2.87 (t, J = 7.0 Hz,
2 H, -CH2-), 3.60 (s, 2 H, -CH2-S), 4.30 (t, J = 7.0 Hz, 2 H, -CH2-
O), 7.15–7.36 (m, 9 H, Ar-H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 34.8, 36.4, 65.8, 126.5, 126.8, 128.4, 128.8, 128.9, 129.7, 134.8,
137.3, 169.5 ppm. MS (ESI): m/z (%) = 295 (100) [M + Na]+.
HRMS (ESI): calcd. for C16H16O2S [M + Na]+ 295.0768; found
295.0742.
Cyclohexylmethyl 2-Phenylethyl Ether (11):[21] 93 mg (71%); a col-
orless liquid. 1H NMR (300 MHz, CDCl3): δ = 0.80–1.10 (m, 2
H, -CH2-), 1.10–1.40 (m, 3 H), 1.50–1.80 (m, 6 H), 2.82 (t, J =
7.3 Hz, 2 H), 3.23 (d, J = 6.4 Hz, 2 H, -CH2-O), 3.61 (t, J = 7.3 Hz,
2 H, -CH2-O), 7.10–7.30 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 25.8, 26.6, 30.0, 36.3, 38.0, 71.9, 76.9, 126.0, 128.2,
128.8, 139.1 ppm. MS (FAB): m/z (%) = 218 (100) [M]+. HRMS
(FAB): calcd. for C15H22O [M + H]+ 219.1749; found 219.1731.
2-Phenylbutyl 2-Phenylethyl Ether (12): 89 mg (58%); a colorless
1
liquid. H NMR (300 MHz, CDCl3): δ = 0.79 (t, J = 7.5 Hz, 3 H
-CH3), 1.47–1.62 (m, 1 H, Ph-CH2-), 1.78–1.91 (m, 1 H, Ph-
CH2-), 2.68–2.78 (m, 1 H Ph-CH-), 2.84 (t, J = 7.5 Hz, 2 H,
-CH2-), 3.55–3.62 (m, 4 H, -CH2-O), 7.16–7.31 (m, 10 H, Ar-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 11.9, 25.5, 36.2, 47.8, 72.0,
75.5, 126.0, 126.2, 127.9, 128.2 (2 C), 128.9, 139.0, 143.0 ppm. MS
(ESI): m/z (%) = 277 (100) [M + Na]+. HRMS (ESI): calcd. for
C18H22O [M + Na]+ 277.1568; found 277.1582.
1-Methylpropyl 3-Phenylpropyl Ether (13): 81 mg (70%); a colorless
1
liquid. H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 7.5 Hz, 3 H,
CH3), 1.12 (d, J = 6.3 Hz, 3 H, CH3), 1.38–1.60 (m, 2 H, -CH2-),
1.83–1.93 (m, 2 H, -CH2-), 2.70 (t, J = 7.5 Hz, 3 H, -CH2-), 3.26–
3.39 (m, 2 H, -CH2-O), 3.45–3.52 (m, 1 H, -CH-O), 7.15–7.30 (m,
5 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 9.9, 19.2, 29.2,
31.7, 32.4, 67.4, 76.5, 125.6, 128.2, 128.4, 142.1 ppm. MS (EI): m/z
(%) = 215 (100) [M + Na]+. HRMS (ESI): calcd. for C13H20O [M
+ Na]+ 215.1411; found 215.1381.
Cyclohexyl 3-Phenylpropyl Ether (14):[20] 66 mg (50%); a colorless
liquid. 1H NMR (300 MHz, CDCl3): δ = 1.15–1.32 (m, 5 H,
-CH2-), 1.50–1.57 (m, 1 H, -CH2-), 1.70–1.77 (m, 2 H, -CH2-),
1.84–1.94 (m, 4 H, -CH2-), 2.69 (t, J = 7.7 Hz, 2 H, -CH2-), 3.15–
3.23 (m, 1 H, -CH-O), 3.45 (t, J = 6.6 Hz, -CH2-O), 7.15–7.29 (m,
5 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.3, 25.9, 31.7,
32.4, 32.5, 66.9, 77.4, 125.5, 128.3, 142.0 ppm. MS (ESI): m/z (%)
= 241 (100) [M + Na]+. HRMS (ESI): calcd. for C15H22O [M +
Na]+ 241.1568; found 241.1556.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR spectra for new compounds.
Acknowledgments
This work was partially supported by a grant from the Japan Pri-
vate School Promotion Foundation supported by the Ministry of
Education, Culture, Sports, Science and Technology (MEXT), and
by a grant from the Center for Colloid and Interface Science
(CCIS) program supported by MEXT. The authors thank Shin-
Etsu Chemical Co., Ltd., for the gift of silanes.
[1] R. C. Larock in Comprehensive Organic Transformations, 2nd
ed., Wiley-VCH, New York, 1999.
1-Methylpropyl 2-Phenylbutyl Ether (15): 64 mg (52%); a colorless
liquid. 1H NMR (500 MHz, CDCl3): δ = 0.76–0.89 (m, 6 H, CH3),
1.05–1.09 (m, 3 H, CH3), 1.36–1.56 (m, 3 H, -CH2-), 1.87–1.98 (m,
1 H, -CH2-), 2.67–2.73 (m, 1 H, Ph-CH-), 3.22–3.28 (m, 1 H, -CH-
O), 3.40–3.49 (m, 1 H, -CH2-O), 3.55–3.62 (m, 1 H, -CH2-O), 7.19
(d, J = 8.0 Hz, 3 H), 7.28 (t, J = 8.0 Hz, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 9.6, 9.8, 11.8, 11.9, 19.1 (2 C), 25.5, 25.6,
29.1, 29.2, 48.2, 48.3, 73.1, 73.2, 76.9, 126.1 (2 C), 127.9, 128.0,
128.1 (2 C), 143.2, 143.3 ppm. MS (ESI): m/z (%) = 229 (100) [M
+ Na]+. HRMS (ESI): calcd. for C14H22O [M + Na]+ 229.1568;
found 229.1543.
[2] G. R. Pettit, D. M. Piatak, J. Org. Chem. 1962, 27, 2127–2130
and references cited therein.
[3] G. A. Kraus, K. A. Frazier, B. D. Roth, M. J. Taschner, K. Ne-
uenschwander, J. Org. Chem. 1981, 46, 2417–2419.
[4] a) D. O. Jang, S. H. Song, D. H. Cho, Tetrahedron 1999, 55,
3479–3488; b) K. C. Nicolaou, M. Sato, E. A. Theodorakis,
N. D. Miller, J. Chem. Soc., Chem. Commun. 1995, 1583–1585.
[5] Boron complex: a) N. A. Morra, B. L. Pagenkopf, Synthesis
2008, 511–514; Ru complex: b) K. Matsubara, T. Iura, T. Maki,
H. Nagashima, J. Org. Chem. 2002, 67, 4985–4988; Ti-Si: c)
M. Yato, K. Homma, A. Ishida, Tetrahedron 2001, 57, 5353–
5359; Mn complex: d) Z. Mao, B. T. Gregg, A. R. Cutler, J.
Am. Chem. Soc. 1995, 117, 10139–10140.
8-[(3-Phenylpropyl)oxy]-1-octene (16): 126 mg (85%); a colorless li-
quid. 1H NMR (500 MHz, CDCl3): δ = 1.33–1.41m, 6 H,
-CH21.54–1.60 (m, 2 H, -CH2-), 1.86–2.06 (m, 2 H, -CH2-), 2.67–
2.70 (m, 2 H, -CH2-CH2=CH), 2.68 (t, J = 7.5 Hz, 2 H, -CH2-Ph),
[6] For selected papers on the deoxygenation of a carbonyl group
by using a two-step procedure, see: a) Ti complex: M. C. Han-
sen, X. Verdaguer, S. L. Buchwald, J. Org. Chem. 1998, 63,
Eur. J. Org. Chem. 0000, 0–0
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N. Sakai, Y. Usui, T. Moriya, R. Ikeda, T. Konakahara
FULL PAPER
2360–2361; b) Raney-Ni: S. L. Baxter, J. S. Bradshaw, J. Org.
Chem. 1981, 46, 831–832.
[7] a) T. Miyai, Y. Onishi, A. Baba, Tetrahedron 1999, 55, 1017–
1026; b) N. Komatsu, J.-y. Ishida, H. Suzuki, Tetrahedron Lett.
1997, 38, 7219–7222; c) M. B. Sassaman, K. D. Kotian,
G. K. S. Prakash, G. A. Olah, J. Org. Chem. 1987, 52, 4314–
4319; d) J.-i. Kato, N. Iwasawa, T. Mukaiyama, Chem. Lett. [14] D. Addis, S. Das, K. Junge, M. Beller, Angew. Chem. 2011, 123,
1985, 14, 743–746.
[8] T. Ohta, M. Kamiya, M. Nobutomo, K. Kusui, I. Furukawa,
Bull. Chem. Soc. Jpn. 2005, 78, 1856–1861.
[9] a) G. Bartoli, M. Bosco, M. Locatelli, E. Marcantoni, P. Mel-
chiorre, L. Sambri, Org. Lett. 2005, 7, 427–430; b) L. Gooßen,
A. Döhring, Adv. Synth. Catal. 2003, 345, 943–947.
[10] For esterification of a carboxylic acid with excess methanol in
the presence of InCl3, see: T. Mineno, H. Kansui, Chem.
Pharm. Bull. 2006, 54, 918–919.
[11] Efficient esterification of a carboxylic acid with an equimolar
amount of an alcohol by using hafnium chloride was already
reported; see: K. Ishihara, S. Ohara, H. Yamamoto, Science
2000, 290, 1140–1142.
ahara, Eur. J. Org. Chem. 2009, 4123–4127; f) N. Sakai, T. Mo-
riya, K. Fujii, T. Konakahara, Synthesis 2008, 3533–3536; g)
N. Sakai, K. Fujii, T. Konakahara, Tetrahedron Lett. 2008, 49,
6873–6875; h) N. Sakai, T. Moriya, T. Konakahara, J. Org.
Chem. 2007, 72, 5920–5922; i) N. Sakai, M. Hirasawa, T.
Konakahara, Tetrahedron Lett. 2005, 46, 6407–6409.
6128; Angew. Chem. Int. Ed. 2011, 50, 6004–6011.
[15] For selected papers on the use of PMHS as a reducing agent,
see: a) L. C. M. Castro, D. Bézier, J.-B. Sortais, C. Darcel, Adv.
Synth. Catal. 2011, 353, 1279–1284; b) R. J. Rahaim, R. E. Ma-
leczka, Org. Lett. 2011, 13, 584–587; c) S. Hanada, E. Tsuts-
umi, Y. Motoyama, H. Nagashima, J. Am. Chem. Soc. 2009,
131, 15032–15040; d) H. Mimoun, J. Org. Chem. 1999, 64,
2582–2589.
[16] Although InBr3-catalyzed Friedel–Crafts-type substitution of
allyl alcohol derivatives with electron-rich aromatic com-
pounds was already reported, no substituted product derived
from allyl alcohol and a solvent, toluene, was observed in our
reaction; see: J. S. Yadav, B. V. Subba Reddy, K. V. Raghaven-
dra Rao, G. G. K. S. Narayana Kumar, Synthesis 2007, 3205–
3210.
[12] For selected papers on the indium/silane-promoted transforma-
tion of carbonyl groups, see: a) Y. Nishimoto, A. Okita, M.
Yasuda, A. Baba, Angew. Chem. 2011, 123, 8782; Angew. [17] H.-B. Sun, B. Li, S. Chen, J. Li, R. Hua, Tetrahedron 2007, 63,
Chem. Int. Ed. 2011, 50, 8623–8625; b) K. Miura, M. Tomita,
Y. Yamada, A. Hosomi, J. Org. Chem. 2007, 72, 787–792; c)
A. Baba, I. Shibata, Chem. Rec. 2005, 5, 323–335; d) M. Ya-
suda, T. Saito, M. Ueba, A. Baba, Angew. Chem. 2004, 116,
1438; Angew. Chem. Int. Ed. 2004, 43, 1414–1416; e) I. Shibata,
H. Kato, T. Ishida, M. Yasuda, A. Baba, Angew. Chem. 2004,
116, 729; Angew. Chem. Int. Ed. 2004, 43, 711–714; f) M. Ya-
suda, Y. Onishi, M. Ueba, T. Miyai, A. Baba, J. Org. Chem.
2001, 66, 7741–7744; g) T. Miyai, M. Ueba, A. Baba, Synlett
1999, 182–184.
10185–10188.
[18] The stoichiometric amount of hydrosilane used was 2 equiv.
though we have noted that when the amount of hydrosilane
used is less than 10 equiv., the yield of ether obtained is mark-
edly reduced; see ref.[13f–13h]
[19] a) Y. Ojima, K. Yamaguchi, N. Mizuno, Adv. Synth. Catal.
2009, 351, 1405–1411; b) G.-B. Liu, H.-Y. Zhao, T. Thiemann,
Adv. Synth. Catal. 2007, 349, 807–811; c) V. Gevorgyan, M.
Rubin, J.-X. Liu, Y. Yamamoto, J. Org. Chem. 2001, 66, 1672–
1675; d) V. Gevorgyan, M. Rubin, S. Benson, J.-X. Liu, Y. Ya-
mamoto, J. Org. Chem. 2000, 65, 6179–6186.
[13] a) N. Sakai, Y. Usui, R. Ikeda, T. Konakahara, Adv. Synth.
Catal. 2011, 353, 3397–3401; b) N. Sakai, K. Nagasawa, R. [20] C. Iwanami, K. Yano, T. Oriyama, Synthesis 2005, 2669–2672.
Ikeda, Y. Nakaike, T. Konakahara, Tetrahedron Lett. 2011, 52,
3133–3136; c) N. Sakai, K. Kawana, R. Ikeda, Y. Nakaike, T.
Konakahara, Eur. J. Org. Chem. 2011, 3178–3183; d) N. Sakai,
K. Fujii, S. Nabeshima, R. Ikeda, T. Konakahara, Chem. Com-
mun. 2010, 46, 3173–3175; e) N. Sakai, K. Moritaka, T. Konak-
[21] T. Harada, T. Mukaiyama, Bull. Chem. Soc. Jpn. 1993, 66, 882–
891.
[22] T. D. Quanch, R. A. Batey, Org. Lett. 2003, 5, 1381–1384.
Received: April 26, 2012
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20552
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Date: 21-06-12 11:26:11
Pages: 7
Ethers from an Aliphatic Carboxylic Acid and an Alcohol
Etherification
A reducing system composed of InBr3 and
an economical hydrosiloxane, PMHS (po-
lymethylhydrosiloxane), enabled one-pot
etherification by using a variety of aliphatic
carboxylic acids and alcohols.
N. Sakai,* Y. Usui, T. Moriya, R. Ikeda,
T. Konakahara .................................. 1–7
One-Pot Sequential Synthesis of Ethers
from an Aliphatic Carboxylic Acid and an
Alcohol by Indium-Catalyzed Deoxygen-
ation of an Ester
Keywords: Indium / Reduction / Silanes /
Ethers / Esters
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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