In(OTf)3 catalyzed reductive etherification of 2-aryloxybenzaldehydes and 2-(arylthio)benzaldehydes

Article abstract of DOI:10.1016/j.tetlet.2019.150955

2-Aryloxybenzaldehydes and 2-(arylthio)benzaldehydes undergo reductive etherification in presence of 5 mol% In(OTf)₃ and stoichiometric amount of Et₃SiH under solvent free conditions to generate novel symmetrical dibenzyl ethers and thioethers in excellent yields. In(OTf)₃ is found to be superior in terms of catalytic activity over the other metal triflates tested for the reaction. Xanthenes and thioxanthenes, as anticipated, could not be obtained under these conditions.

Full text of DOI:10.1016/j.tetlet.2019.150955

Accepted Manuscript
In(OTf)3 Catalyzed Reductive Etherification of 2-Aryloxybenzaldehydes and 2-
(Arylthio)benzaldehydes
Anamika Prajapati, Mahendra Kumar, Ranjit Thakuria, Ashok K. Basak
PII:
S0040-4039(19)30703-8
https://doi.org/10.1016/j.tetlet.2019.150955
150955
DOI:
Article Number:
Reference:
TETL 150955
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
24 June 2019
16 July 2019
Please cite this article as: Prajapati, A., Kumar, M., Thakuria, R., Basak, A.K., In(OTf)3 Catalyzed Reductive
Etherification of 2-Aryloxybenzaldehydes and 2-(Arylthio)benzaldehydes, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.150955
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Graphical Abstract
In(OTf)3 catalyzed reductive etherification of
Leave this area blank for abstract info.
2-aryloxybenzaldehydes
(arylthio)benzaldehydes
and
2-
Anamika Prajapati, Mahendra Kumar, Ranjit Thakuria and Ashok K. Basak
O
R
R
O
5 mol% In(OTf)3
X
Et3SiH, neat
rt
X
X
R'
R
X = O, S
R'
R'
13 examples
upto 94% yields

1
Tetrahedron Letters
journal homepage: www.elsevier.com
In(OTf)3 Catalyzed Reductive Etherification of 2-Aryloxybenzaldehydes and 2-
(Arylthio)benzaldehydes
c
Anamika Prajapati,a Mahendra Kumar,a Ranjit Thakuria,b Ashok K. Basak
aDepartment of Chemistry, University of Rajasthan, JLN Marg, Jaipur-302004, India
bDepartment of Chemistry, Gauhati University, Guwahati-781014, India
cDepartment of Chemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2-Aryloxybenzaldehydes and 2-(arylthio)benzaldehydes undergo reductive etherification in
presence of 5 mol% In(OTf)3 and stoichiometric amount of Et3SiH under solvent free conditions
to generate novel symmetrical dibenzyl ethers and thioethers in excellent yields. In(OTf)3 is
found to be superior in terms of catalytic activity over the other metal triflates tested for the
reaction. Xanthenes and thioxanthenes, as anticipated, could not be obtained under these
conditions.
Available online
Keywords:
2-Aryloxybenzaldehyde
2-Arylthiobenzaldehyde
Reductive etherification
Dibenzyl ether
Ethers are an important class of organic compounds. Simple
and efficient synthesis of ethers is still a subject of broad
attention.1 Benzyl ethers have been explored as coupling partner
due to their easy availability and stability.2 Dibenzyl ethers and
its derivatives have also gained significant synthetic importance.
For instance, Nakai et al. demonstrated the enantioselective [1,2]-
Wittig rearrangement of dibenzyl ethers.3 Palladium and copper
catalyzed oxidative coupling of arene C-H with dibenzyl ethers
have also been developed4 wherein dibenzyl ether serves as an
acyl equivalent. Recently, Shi et al. have utilized dibenzyl ethers
for nickel-catalyzed deoxygenation reaction to generate new sp3-
sp3 bond leading to the synthesis of diaryl ethanes.5 Sakai et al.
converted dibenzyl ethers into dibenzyl sulfide and selenides in
presence of InI3 as catalyst.6 Symmetrical dibenzyl ethers are
readily accessible via reductive etherification of carbonyl
compounds. The reactions are generally carried out in presence
of a Lewis or Bronsted acid and silicon based reducing agent.7
Many of these reagents require anhydrous conditions and many
fold excess of Bronsted acid.8 Therefore, a simple, convenient
and efficient method for the generation of symmetrical benzyl
ethers is still desirable. Moreover, the synthesis of dibenzyl ether
and thioether from 2-aryloxybenzaldehydes and 2-
(arylthio)benzaldehydes is not reported in the literature.
conversion of 2-substituted benzaldehydes into polycyclic
aromatic compounds. 2-Aryloxybenzaldehydes can be converted
into xanthenones under oxidative conditions catalyzed transition
metal.10 The xanthenones can be reduced to the corresponding
xanthenes under mild reaction conditions.11 Panda et al.
developed Sc(OTf)3 catalyzed one-pot domino process which
relies upon cationic cyclization to generate 9-aryl substituted
xanthenes in high yields (Scheme 1b).12 Takai et al. showed that
2-substituted benzaldehydes could be converted into anthracenes
and acridines in presence of catalytic amount of In(OTf)3
(Scheme 1a).13 The reaction relies upon Friedel-Crafts type
cyclization followed by aromatization at high temperature. As
depicted in Scheme 2, we hypothesized that xanthene could be
conveniently synthesized from 2-aryloxybenzaldehyde in
presence of a reducing agent.
O
O
catalyst
oxidant
........................ (a)
....................... (b)
X
X
X = O, NR
O
Ar
Sc(OTf)3
ArH
X
O
X = O, S
2-Aryloxybenzaldehydes
and
2-(arylthio)benzaldehydes
O
provide a convenient access to xanthenes and thioxanthenes.
These aldehydes are readily generated from commercially
available 2-fluorobenzaldehydes via aromatic nucleophilic
substitution reactions with phenols and thiophenols under simple
reaction conditions which often lead to the 2-
aryloxybenzaldehydes and 2-arylthiobenzaldehydes in very high
yields.9 Scheme 1 represents selected important methods for the
In(OTf)3
....................... (c)
X
X
H
X = CH, N
Scheme 1: Methods for the conversion of 2-substituted
benzaldehydes into polycyclic aromatic compounds.

2
Tetrahedron
However, formation of the anticipated xanthene 3 was not
Table 2: Reductive etherification of 2-aryloxybenzaldehydes and 2-
(arylthio)benzaldehydesa
observed and symmetrical dibenzyl ether 4a was obtained in 65%
yield along with reduced aldehyde.
O
R
R
OH
O
5 mol% In(OTf)3
Et3SiH, neat
X
X
X
R'
R
1
4
O
O
O
O
3
2
X = O, S
R'
R'
not observed
10 mol% Sc(OTf)3
Et3SiH, DCM, reflux
not observed
2-O-aryl/S-aryl
benzaldehyde 1
1a
dibenzyl ether/thioether
O
entry
4
65%
O
O
4a
O
Scheme 2: Attempted cyclization of O-phenyl salicylaldehyde
O
O
O
O
1a
a
A short combination of metal triflates and solvent were tested for
the reaction and the results are presented in Table 1. Formation of
xanthene 3 was not observed under these conditions and the
4a
5 min, rt, 90%b
O
Table 1: Screening of metal triflates and reducing agents
OMe
O
O
O
O
b
c
d
4b
OH
O
1b
MeO
O
conditions
OMe
O
O
rt, 5 min, 92%
O
5
O
4a
1a
O
Me
Me
O
Me
Me
Me
Me
entry
conditionsa
yield (%)
O
O
O
4c
1c
a
b
c
d
e
f
10 mol% Sc(OTf)3, Et3SiH, DCM, reflux, 2 h
10 mol% Sc(OTf)3, Et3SiH, CH3CN, 40 oC, 2 h
10 mol% Yb(OTf)3, Et3SiH, DCM, reflux, 2 h
10 mol% Cu(OTf)2, Et3SiH, DCM, reflux, 3 h
10 mol% Fe(OTf)3, Et3SiH, DCM, reflux, 2 h
10 mol% In(OTf)3, Et3SiH, DCM, reflux, 2 h
10 mol% In(OTf)3, Et3SiH, neat, rt, 5 min
5 mol% In(OTf)3, Et3SiH, neat, rt, 5 min
5 mol% In(OTf)3, Ph2SiHMe, neat, rt, 10 min
5 mol% In(OTf)3, PMHS, neat, rt, 10 min
5 mol% In(OTf)3, DCE, 80 oC, 1 h
65b
62
70
68
74
84
94
92
90
88
NR
rt, 5 min, 90%
Br
O
Br
Br
O
O
1d
O
O
4d
g
h
i
rt, 6 min, 87%
O
O
j
O
O
O
e
k
1e
4e
a all reactions were carried out under nitrogen atmosphere at using
2.5 eq of reducing agent at 0.2 M solvent concentration; b15% alcohol 5 was
isolated; NR = no reaction
rt, 10 min, 86%
Cl
O
Me
Cl
Cl
O
symmetrical dibenzyl ether 4a was isolated in variable yields
in short reaction time. When Sc(OTf)3 was used as catalyst, diary
ether 4a was obtained in 65% and 62% yields in DCM and
CH3CN respectively. These reactions also generated alcohol 5 in
12% and 15% yields respectively. Use of 10 mol% Yb(OTf)3 and
Cu(OTf)2 as catalyst in DCM provided dibenzyl ether 4a in 70%
and 68% yields respectively. Employing Fe(OTf)3 as the catalyst,
the dibenzyl ether 4a could be obtained in 74% yields. Improved
yield (84%) was obtained when 10 mol% In(OTf)3 was used as
the catalyst. However, the best yield was obtained under solvent
free conditions in short reaction time (entry, g, Table 1). 5 mol%
of In(OTf)3 was found to catalyze the reaction efficiently under
solvent free conditions at room temperatue (35 oC). Use of
methyldipheylsilane and polymethylhydrosiloxane (PMHS) as
the reducing agent provided the dibenzyl ether 4a in good yields
under solvent free conditions. No reaction was observed in the
Me
Me
Me
Me
O
O
O
f
Me
1f
4f
rt, 5 min, 90%
Cl
O
Cl
Cl
OMe
O
O
O
O
g
h
4g
1g
MeO
OMe
40 oC, 3 min, 89%
O
Me Me
Me
O
O
O
O
4h
Me
1h
Me
Me
o
absence of reducing agent even after heating at 80 C for 1 hour
(entry k, Table 1)
Me
Me
Me
rt, 5 min, 94%

3
under the standard reaction conditions. This suggests that the
reaction most likely does not pass via alcohol intermediate.
O
O
Me
O
Me
O
O
Me
i
1i
Me
Me
Me
Me
4i
Me
Me
rt, 5 min, 92%
O
Me
Cl
O
O
O
O
j
1j
4j
Cl
Cl
Me
Me
rt, 5 min, 90%
O
O
S
S
S
k
4k
Figure 1: ORTEP diagram for compound 4k with 35%
1k
probability ellipsoid
rt, 5 min, 86%
O
Me
O
In(OTf)3
Et3Si
O
S
S
S
H
O
l
4l
1l
O
Me
O
Me
+
OPh
rt, 5 min, 90%
PhO
6
1a
(a)
OPh
PhO
O
Cl
O
-Et3SiO
S
S
S
m
Et3SiH
O
1m
4m
O
Cl
Cl
4a
-Et3SiOSiEt3
rt, 5 min, 88%
7
OPh
PhO
OPh
PhO
aAll reactions were carried out in 0.30 mmol scale using 1.0 eq
aldehyde, 5 mol% In(OTf)3 and 2.5 eq of Et3SiH without any
solvent; bisolated yield after column chromatography
OH
O
5 mol% In(OTf)3
(b)
4a
Et3SiH, DCE
60 oC, 3 h
45%
OPh
OPh
PhO
5
Reductive etherification under solvent-free conditions using 5
mol% In(OTf)3 as catalyst was tested on the various 2-
aryloxybenzaldehydes and 2-(arylthio)benzaldehydes generated
from commercially available materials via aromatic nucleophilic
substitution reaction (see supporting information). The results of
the symmetrical dibenzyl ether forming reactions are shown in
Table 2. Dibenzyl ether formations were usually very clean and
high yielding requiring short reaction time (3-10 min). Most of
the reactions occurred at room temperature. The reductive
etherification reactions were effective with substrate derived
from electron rich phenols (1b, 1c, 1f, 1g-1i) as well as electron
deficient phenols (1i). To our delight, the diary ether forming
reaction were equally effective with 2-(arylthio)benzaldehydes
(1j-1k) generated from electron donating as well as electron
withdrawing group containing thiophenols. A solution 4k in
hexanes upon storage in a refrigerator for three weeks generated
crystals that were found to be suitable for single crystal XRD
studies. As shown in Figure 1, the data showed that 4k has a
linear orientation of the two benzyl ether forming phenyl rings.
The two thioaryl rings orient themselves away from each other.
Scheme 3: Plausible mechanism of In(OTf)3-catalyzed reductive
etherification reaction
In summary, In(OTf)3-catalyzed reductive etherification of 2-
aryloxybenzaldehydes and 2-(arylthio)benzaldehydes using
Et3SiH as the reducing agent under solvent-free conditions has
been developed. The method generates synthetically important
dibenzyl ethers in excellent yields. The dibenzyl ethers may find
importance as ligand in transition metal catalyzed coupling
reactions. The mild reaction conditions might be useful in the
reductive etherification of more complex substrates.
Acknowledgments
AP thanks CSIR, New Delhi for a research fellowship. We thank
MRC, MNIT Jaipur for NMR spectra. We are thankful to USIC,
University of Rajasthan, Jaipur for HRMS data. Research grants
(Grant No. YSS/2014/000957) from SERB, New Delhi is
gratefully acknowledged.
The plausible reaction mechanism of the reaction is depicted
in Scheme 3. Intermolecular condensation of two molecules of
aldehyde 1a generates intermediate 6 which is reduced with
Et3SiH to oxonium ion 7. Reduction of the oxonium ion with
another molecule of Et3SiH generates the dibenzyl ether 4a.
Direct etherification with alcohol 5 is very slow and low yielding
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Supplementary Material
Supplementary material (experimental procedure, analytical
1
data and copies of H & 13C NMR spectra) is available for this
article.

5
 Novel dibenzyl ethers/thioethers synthesis
 Solvent free conditions
 High yielding reactions