Reductive coupling reaction of aldehydes using indium(III) triflate as the catalyst

Article abstract of DOI:10.1016/j.tetlet.2014.05.079

A reductive coupling reaction was effectively developed to convert an aldehyde to its symmetrical ether. The successful reactions required Et ₃SiH and CH₂Cl₂ as the suitable solvent in the presence of a catalytic amount of In(OTf)₃. Various aldehydes were subjected to the method, and each afforded the expected ethers in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.05.079

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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Reductive coupling reaction of aldehydes using indium(III) triflate
as the catalyst
a
a
b
c
Tomoko Mineno a, , Rie Tsukagoshi , Tsubasa Iijima , Kazuki Watanabe , Hiroyuki Miyashita ,
⇑
Hitoshi Yoshimitsu c
a Laboratory of Medicinal Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui, Takasaki, Gunma 370-0033, Japan
b Laboratory of Organic Chemistry for Life Sciences, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui, Takasaki, Gunma 370-0033, Japan
c Laboratory of Natural Medicine, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A reductive coupling reaction was effectively developed to convert an aldehyde to its symmetrical ether.
The successful reactions required Et3SiH and CH2Cl2 as the suitable solvent in the presence of a catalytic
amount of In(OTf)3. Various aldehydes were subjected to the method, and each afforded the expected
ethers in good to excellent yields.
Received 27 February 2014
Revised 7 May 2014
Accepted 16 May 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Reductive coupling reaction
Aldehydes
Indium(III) triflate
Catalyst
Ethers are a recognizable class of organic components in which
two hydrocarbons are bound to both sides of one oxygen atom.
Ether moieties are found in a couple of historically important nat-
ural products that made up early remedies in traditional natural
medicines. Many studies in the fields of chemistry and pharmacol-
ogy have included therapeutic natural products to date.1 The most
venerable examples of ether-containing natural products include
morphine, digitoxin, paclitaxel, quinine, artemisinin, and halichon-
drin B. Morphine is an opium alkaloid that is used as a pain relie-
ver, and digitoxin is a glycoside that exhibits cardiotonic activity.
Paclitaxel is a widely used pharmaceutical agent under the name
of Taxol for the treatment of breast cancer. Both quinine and arte-
misinin show anti-malarial activity, although the mechanism of
action toward a cure is different. Halichondrin B was selected for
further structural development as a cell proliferation inhibitor in
the treatment of breast carcinoma. Synthetic chemistry was
accomplished by Avery et al. for the total synthesis of artemisinin
along with its analogues.2,3 Also, halichondrin B was successfully
synthesized and reported by Kishi et al. in 1992.4
place with ether, and many modifications for homocoupling and
heterocoupling have been introduced, including the reductive
etherification of carbonyl compounds. Several reports utilized
organosilicon reagents such as Et3SiH, Me3SiH, and PhSiH3 in the
presence of Lewis acid activators, including BF3ÁEt2O,6 TMSI,7,8
TMSOTf,9,10 BiBr3,11 BiCl3,12 FeCl3,13,14 TrClO4,15 and SbI3.16 Prece-
dently, syntheses of symmetrical ethers by means of reductive
etherification of aldehydes using 1,1,3,3-tetramethyldisiloxane
(TMDS) and Cu(OTf)2 have been reported with efficient results.17
Table 1
The search for the appropriate combination of silane reagents and solvents
silane, In(OTf)3
solvent, r.t.
CHO
O
Cl
Cl
Cl
Entrya
Silane
Solvent
Time
Yieldb (%)
1
2
3
4
5
6
7
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
PhSiH3
PhMe2SiH
CH3CN
THF
24 h
24 h
48 h
24 h
24 h
24 h
3 days
N.R.
N.R.
N.R.
60
90
N.R.
46
The Williamson ether synthesis is the most fundamental
method for the preparation of ethers, in which an alkoxide is
reacted with an alkyl halide.5 Since the introduction of the
Williamson method, decades of intensive research have taken
Toluene
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
a
⇑
Corresponding author. Tel.: +81 27 352 1180; fax: +81 27 352 1118.
E-mail address: mineno@takasaki-u.ac.jp (T. Mineno).
For all reactions, 4 equiv of silane and 10 mol % of In(OTf)3 were used.
Isolated yields.
b
http://dx.doi.org/10.1016/j.tetlet.2014.05.079
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mineno, T.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.079

2
T. Mineno et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 2
The reductive coupling reaction of aldehydes
Et3SiH, In(OTf)3
O
R
O
R
R
H
CH2Cl2, r.t.
Entrya
1
Substrate
Product
Time (h)
24
Yieldb (%)
90
CHO
O
Cl
Cl
Cl
Me
CHO
CHO
Me
Me
O
2
3
40
43
84
80
O
O
Me
Me
Me
Me
Me
Me
CHO
4
187
63
Me
Me
Me
CHO
CHO
CHO
CHO
O
O
5
6
7
20
4
89
90
85
tBu
Ph
F
tBu
tBu
Ph
F
Ph
O
24
F
O
8
9
17
5
63
74
97
Br
Br
Br
TBDPSO
CHO
TBDPSO
OTBDPS
O
MeO
CHO
MeO
OMe
O
O
10
4
TsO
MeO
TsO
MeO
OTs
OMe
CHO
11
12
4
76
73
BzO
BzO
OBz
CHO
O
23
CHO
CHO
O
O
13
14
23
17
80
87
a
For all reactions, 4 equiv of silane and 10 mol % of In(OTf)3 were used.
Isolated yields.
b
Other systems for the preparation of ethers using catalytic zinc
reagents have also been demonstrated.18,19 Consequently, a recent
trend has extended the examination of etherification and applied
Lewis acids of indium, such as InCl3 and InBr3.20,21
using chlorinated solvents led to the desired symmetrical ethers
(Table 1, entries 4 and 5).19 In particular, CH2Cl2 was the most effi-
cient solvent and gave an excellent yield of 90%. This high yield
might be due to the suitable polarity of CH2Cl2, in which the ether
products could remain stable. The use of other silane reagents was
then investigated, keeping CH2Cl2 as the solvent. However,
replacement with other silane reagents worsened the results
(Table 1, entries 6 and 7).
With the successful conditions for a reductive coupling reaction
in hand, various aldehydes were subjected to this method in order
to pursue the scope and applicability. As shown in Table 2, many
benzaldehyde derivatives were efficiently transformed to symmet-
rical ethers.29–35 The 3- and 4-methyl substituted benzaldehyde
derivatives furnished the products in high yields (Table 2, entries
2 and 3),29 and 3,5-dimethyl benzaldehyde also gave a good yield,
despite a longer reaction time (Table 2, entry 4). Furthermore, the
aldehydes with other hydrocarbon and halogen substituents suc-
cessfully afforded the corresponding ethers in good to excellent
yields (Table 2, entries 5–8).30–32 Since the free phenol moiety
affected reaction course, the protection of phenol groups was thus
We have focused on the utility of an indium reagent, and sev-
eral studies have reported the catalytic application of trivalent
In(OTf)3, as well as that of indium metal.22–28 In our ongoing efforts
to explore indium-utilized chemistry, we have found that the cat-
alytic use of In(OTf)3 could enhance the reductive coupling reac-
tion of aldehydes, converting the initial aldehydes to their
symmetrical ethers. Herein, we report the details of our study.
In the initial search for the appropriate combination of silane
reagents and solvents, we attempted preliminary experiments
using 4-chlorobenzaldehyde as the starting substrate. Based on
the precedent examples, we considered Et3SiH as our first choice,
and several solvents were examined employing In(OTf)3 as the cat-
alyst (Table 1). The reactions using CH3CN, THF, and toluene were
terminated because there was no reaction, and the starting mate-
rial of 4-chlorobenzaldehyde was recovered intact after 24 or
48 h (Table 1, entries 1–3). On the other hand, transformations
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T. Mineno et al. / Tetrahedron Letters xxx (2014) xxx–xxx
13. Iwanami, K.; Seo, H.; Tobita, Y.; Oriyama, T. Synthesis 2005, 183–186.
3
advanced. The tert-butyldiphenylsilyl (TBDPS) protecting group
gave good results in maintaining the function of protection
(Table 2, entry 9). Also, tosyl (Ts) and benzoyl (Bz) groups pro-
tected vanillin, a natural product found in vanilla beans, and the
substrates were effectively transformed to the expected ethers
(Table 2, entries 10 and 11). Etherification was then extended to
bicyclic and aliphatic compounds under the same reaction pro-
cesses. The 1- and 2-naphthaldehydes gave the corresponding
ethers in sufficient yields (Table 2, entries 12 and 13),33 and the
reaction of 3-phenylpropanal also resulted in a high yield of its
symmetrical ether (Table 2, entry 14).17,34 Compared with prece-
dent report using TMDS and Cu(OTf)2 to prepare symmetrical
ethers,17 we extended the array of benzaldehyde derivatives and
bicyclic aromatics, and validated the method with Et3SiH and
In(OTf)3. Furthermore, protecting groups attempted were not
cleaved by these reaction conditions.
In summary, by employing In(OTf)3 as a catalyst, a reductive
coupling reaction was effectively developed that converts an alde-
hyde to its symmetrical ether. Various aldehydes were subjected to
this method, and each afforded the expected ethers in good to
excellent yields. A tolerance of protecting groups such as TBDPS,
Ts, and Bz was also revealed. Further study of the application of
this method is ongoing.
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Chem. Pharm. Bull. 2013, 61, 870–872.
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7153–7154.
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General experimental procedure: The typical experimental proce-
dure included
a starting material of 4-chlorobenzaldehyde
(141 mg, 1 mmol) dissolved in dehydrated CH2Cl2 (10 mL) in a
100 mL flask equipped with a magnetic stirrer. Subsequently,
In(OTf)3 (56 mg, 10 mol %) was added at room temperature. Et3SiH
(0.64 mL, 4 mmol) was added via a syringe, and the reaction
mixture was stirred under argon at room temperature for 24 h.
The reaction completion was monitored by TLC, and the reaction
mixture was condensed using a rotary evaporator. Flash column
chromatography on silica gel furnished the desired ether product,
which was confirmed by spectroscopy.
35. Experimental data for Table 2.
Bis(3-methyl)benzyl ether (Table 2, entry 2): 1H NMR (500 MHz, CDCl3): d 7.23 (t,
2H, J = 7.5 Hz), 7.18–7.14 (m, 4H), 7.01 (d, 2H, J = 7.5 Hz), 4.51 (s, 4H), 2.34 (s,
6H); 13C NMR (125 MHz, CDCl3): d 138.2, 138.0, 128.5, 128.3, 128.2, 124.8,
72.1, 21.3; FT-IR (NaCl): 3026.41, 2920.32, 2856.67, 1610.61, 1489.10, 1456.30,
1354.07, 1159.26, 1082.10, 777.34, 694.40 cmÀ1; MS (ESI+) m/z [M+H]+ calcd
for C16H18O, 227; found, 227.
Bis(3,5-dimethyl)benzyl ether (Table 2, entry 4): 1H NMR (500 MHz, CDCl3): d
7.04 (s, 4H), 6.98 (s, 2H), 4.54 (s, 4H), 2.37 (s, 12H); 13C NMR (125 MHz, CDCl3):
d 138.2, 137.9, 129.2, 125.7, 72.2, 21.2; HRMS (ESI+) m/z [M+Na]+ calcd for
Acknowledgment
C18H22O, 277.1563; found, 277.1586.
Bis(4-phenyl)benzyl ether (Table 2, entry 6): 1H NMR (500 MHz, CDCl3): d 7.62–
7.60 (m, 8H), 7.48–7.43 (m, 8H), 7.36 (t, 2H, J = 7.5 Hz), 4.65 (s, 4H); 13C NMR
(125 MHz, CDCl3): d 140.9, 140.6, 137.3, 128.8, 128.3, 127.3, 127.2, 127.1, 71.9;
HRMS (ESI+) m/z [M+Na]+ calcd for C26H22O, 373.1563; found, 373.1593.
Bis(3-tert-butyldiphenylsilyloxy)benzyl ether (Table 2, entry 9): 1H NMR
(500 MHz, CDCl3): d 7.90 (d, 8H, J = 8.0 Hz), 7.54–7.47 (m, 12H), 7.16 (t, 2H,
J = 8.0 Hz), 6.97–6.93 (m, 4H), 6.83 (d, 2H, J = 8.5 Hz), 4.39 (s, 4H), 1.29 (s, 18H);
13C NMR (125 MHz, CDCl3): d 155.6, 139.6, 135.5, 132.8, 129.8, 129.1, 127.7,
120.4, 119.1, 118.8, 71.4, 26.5, 19.4; HRMS (ESI+) m/z [M+Na]+ calcd for
This study was partially supported by a Grant from the Naito
Foundation.
References and notes
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C46H50O3Si2, 729.3191; found, 729.3206.
Bis(3-methoxy-4-tosylhydroxy)benzyl Ether (Table 2, entry 10): 1H NMR
(500 MHz, CDCl3): d 7.76 (d, 4H, J = 8.0 Hz), 7.30 (d, 4H, J = 8.0 Hz), 7.10 (d,
2H, J = 8.0 Hz), 6.86–6.83 (m, 4H), 4.49 (s, 4H), 3.57 (s, 6H), 2.45 (s, 6H); 13C
NMR (125 MHz, CDCl3): d 151.6, 145.0, 138.1, 137.5, 132.9, 129.2, 128.4, 123.6,
119.4, 111.6, 71.6, 55.4, 21.5; HRMS (ESI+) m/z [M+Na]+ calcd for C30H30O9S2,
621.1223; found, 621.1246.
Bis(4-benzoyloxy-3-methoxy)benzyl ether (Table 2, entry 11): 1H NMR (500 MHz,
CDCl3): d 8.25 (d, 4H, J = 8.0 Hz), 7.64 (t, 2H, J = 7.5 Hz), 7.52 (t, 4H, J = 8.0 Hz),
7.17 (d, 2H, J = 8.0 Hz), 7.09 (d, 2H, J = 2.0 Hz), 7.01 (dd, 2H, J = 8.0, 1.5 Hz), 4.62
(s, 4H), 3.84 (s, 6H); 13C NMR (125 MHz, CDCl3): d 164.7, 151.3, 139.3, 137.1,
133.4, 130.2, 129.3, 128.4, 122.7, 119.8, 111.7, 71.7, 55.8; HRMS (ESI+) m/z
[M+Na]+ calcd for C30H26O7, 521.1571; found, 521.1575.
Bis(2-naphthyl)methyl ether (Table 2, entry 13): 1H NMR (500 MHz, CDCl3): d
7.88–7.85 (m, 8H), 7.54 (dd, 2H, J = 8.5, 1.5 Hz), 7.52–7.47 (m, 4H), 4.78 (s, 4H);
13C NMR (125 MHz, CDCl3): d 135.7, 133.3, 133.0, 128.2, 127.9, 127.7, 126.6,
126.1, 125.9, 125.8, 72.2; HRMS (ESI+) m/z [M+Na]+ calcd for C22H18O,
321.1250; found, 321.1253.
Please cite this article in press as: Mineno, T.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.079