An Efficient Ga(OTf)3/Isopropanol Catalytic System for Direct Reduction of Benzylic Alcohols

Article abstract of DOI:10.1002/adsc.201801135

This study aims to report the first gallium-catalyzed direct reduction of benzylic alcohols using isopropanol as a reductant. The reaction proceeds via gallium catalyst-assisted hydride transfer of the in situ-generated benzylic isopropyl ether. The method generates only water and acetone as byproducts and thus provides an atom-economic and environmentally friendly approach to the synthesis of di- and triarylmethanes, which are important substructures in various bioactive compounds and functional materials. (Figure presented.).

Full text of DOI:10.1002/adsc.201801135

Title: An Efficient Ga(OTf)3/Isopropanol Catalytic System for Direct
Reduction of Benzylic Alcohols
Authors: Masahiro Sai
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10.1002/adsc.201801135
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
An Efficient Ga(OTf)3/Isopropanol Catalytic System for Direct
Reduction of Benzylic Alcohols
Masahiro Saia,*
a
Research Foundation ITSUU Laboratory, C1232 Kanagawa Science Park R & D Building, 3-2-1 Sakado, Takatsu-ku,
Kawasaki, Kanagawa 213-0012, Japan
Phone: (+81)-44-819-4044; fax: (+81)-44-819-4483; e-mail: msai@itsuu.or.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Since the pioneering work on the direct reduction of
catalyzed direct reduction of benzylic alcohols using alcohols by Baba,[10d] several catalytic systems
Abstract. This study aims to report the first gallium-
isopropanol as a reductant. The reaction proceeds via
gallium catalyst-assisted hydride transfer of the in situ-
generated benzylic isopropyl ether. The method generates
only water and acetone as byproducts and thus provides an
atom-economic and environmentally friendly approach to
the synthesis of di- and triarylmethanes, which are
important substructures in various bioactive compounds
and functional materials.
capable of such transformations have been
developed,[10,11] most of which utilize hydrosilanes as
the reductant.[10] Herein, we have attempted to
develop a new catalytic system based on isopropanol
as a hydride source because the only byproducts of
this reaction are water and acetone. Although
isopropanol is well-known as a hydride donor in
various reactions, such as Meerwein–Ponndorf–
Verley (MPV) reduction[12] and the transfer
hydrogenation of carbonyl compounds,[13] there are
no reports of the use of isopropanol in the direct
reduction of alcohols. In our previous study, we
demonstrated for the first time that LiPF6 can
effectively reduce allylic alcohols to alkenes using
isopropanol as a reductant.[14] However, this catalytic
system is only applicable to highly specialized allylic
alcohols, greatly limiting its utility. Accordingly, in
the current study, we have developed a novel
Ga(OTf)3/isopropanol system that exhibits high
catalytic activity for the direct reduction of benzylic
alcohols to diarylmethanes (Scheme 1).
Keywords: benzylic alcohols; gallium; reduction; hydride
transfer; diarylmethanes
Diarylmethanes are ubiquitous structural motifs that
are found in many pharmaceuticals.[1] They are also
prevalent subunits in a variety of supramolecules.[2]
Diarylmethanes are traditionally synthesized by
Friedel–Crafts benzylation of arenes, but this reaction
suffers from drawbacks such as low regioselectivity
and the need to employ large amounts of acids.[3]
Furthermore, significant advances have been made in
the field of transition-metal-catalyzed cross-coupling
reactions. As a result, the most common strategy
currently used to synthesize diarylmethanes is the
cross-coupling of benzylic halides[4] or their
surrogates[5] with aryl nucleophiles, or that of aryl
electrophiles with benzylic nucleophiles.[6] However,
this approach requires additional steps for substrate
preparation and produces significant amounts of
organic and inorganic waste. To overcome the
disadvantages of these strategies, significant research
effort has recently been dedicated to the direct
coupling of benzylic alcohols.[7] On the other hand,
the direct deoxygenation of diarylmethanols appears
to be an attractive alternative for the synthesis of
diarylmethanes because a broad range of structurally
and electronically diverse diarylmethanols is readily
accessible from the corresponding aldehydes and aryl
metals. However, due to the poor leaving ability of
the hydroxy group, it is necessary to convert alcohols
to the corresponding halides or pseudohalides prior to
reduction, which can be a significant drawback.[8,9]
Ar2
H
Ar1
X
Friedel–Crafts
acid
Ar2
Ar2
M
Ar1
Ar1
X
cross-coupling
metal
reductant
Lewis acid
"
H
OH
direct
reduction
Ar1
Ar2
Ar1
Ar2
X
M
benzylic alcohols
diarylmethanes
This Work: (direct reduction of benzylic alcohols to diarylmethanes)
i
PrOH
"
OH
H
cat. Ga(OTf)3
PhCF3, reflux
Ar1
Ar2
Ar1
Ar2
d–
benzylic alcohols
diarylmethanes
Ga(OTf)3
H
O
H2O
byproduct
acetone
d+
Ar1
Ar2
hydride transfer
Scheme 1. Various synthetic approaches to diarylmethanes.
1
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10.1002/adsc.201801135
Advanced Synthesis & Catalysis
Our investigation began with the screening of
investigated (Table 2). Benzylic alcohols containing
electron-neutral (1b), electron-rich (1c–1g), and
slightly electron-poor (1h–1j) aromatic rings undergo
the direct reduction smoothly to afford the
corresponding diarylmethanes 2b–2j in 80–99%
yields.[19,20] Furthermore, the present catalytic system
tolerates carbonyl groups that are susceptible to
reduction, providing 2k and 2l in moderate yields.[21]
Xanthydrol 1m is also a suitable substrate. Although
the reaction of 1k and 1l, which bear strong electron-
withdrawing groups, result in moderate yields,
substrates 1n–1s, which have both electron-donating
and -withdrawing groups, exhibit high reactivities.
Lewis acid catalysts for the direct reduction of
benzhydrol 1a with isopropanol (Table 1).[15]
Interestingly, LiPF6, which was the optimal catalyst
in our previous study,[14] does not catalyze the
reaction, resulting in the formation of benzylic
isopropyl ether 3 (entry 1).[16] To realize the desired
reduction, it is necessary to cleave the C–O bond of
ether 3 effectively. Thus, the oxophilic group 13
catalysts were examined. Although BF3∙Et2O and
AlCl3 were incapable of the desired transformation
(entries 2 and 3), Ga(OTf)3 and In(OTf)3 were
particularly effective in promoting the desired
transformation, delivering 2a in >99% and 73%
yields, respectively (entries 4 and 5). Further
investigation using Sc(OTf)3, Bi(OTf)3, and Fe(OTf)3
resulted in slightly inferior yield of 2a (entries 6–8),
while other metal triflates such as Cu(OTf)2, AgOTf,
and Zn(OTf)2, provided poor results (entries 9–11).
These results suggest that strong hard Lewis acids are
effective for the reaction because such catalysts are
suitable to enhance the C–O bond cleavage and
confer a longer lifetime to the benzylic cation
intermediate, providing a chance for effective hydride
transfer. The use of TfOH also provided 2a in
moderate yield (entry 12).[17] Solvent screening
identified PhCF3, which has recently emerged as a
greener alternative to chlorinated solvents, as the
optimal solvent for this system (entry 13).[18]
Table 2. Substrate scope of secondary benzylic alcohols
1.[a]
iPrOH (5 equiv.)
OH
H
Ga(OTf)3 (5 mol%)
PhCF3, reflux, 12 h
Ar1
Ar2
Ar1
Ph
Ar2
1
2
H
H
H
Me
Ph
Ph
Ph
Ph
Me
Me
2d
92%
2b
>99%
Me
2c
94%
H
H
H
O
O
Ph
Ph
Table 1. Optimization of reaction conditions.[a]
Me
Me
OMe
2e
93%
2f
90%
2g
80%[b]
iPrOH (5 equiv.)
H
H
H
OiPr
Ph
OH
H
catalyst (5 mol%)
Ph
Ph
Ph
Ph
solvent, reflux, 12 h
Ph
Ph
Ph
Ph
Ph
1a
2a
3
F
Cl
Br
2h
91%
2i
96%
2j
89%
H
Yield [%][b]
Entry Catalyst
Solvent
H
H
2a
3
1
2
3
4
5
6
7
8
LiPF6
BF3·Et2O
AlCl3
Ga(OTf)3
In(OTf)3
Sc(OTf)3
Bi(OTf)3
Fe(OTf)3
Cu(OTf)2
AgOTf
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
PhCF3
0
3
0
>99
73
82
60
92
8
94
89
31
0
21
15
42
6
85
64
96
47
Ph
CO2Me
Ac
O
2l
41%[d]
2m
54%
2k
65%[c]
H
H
Me
CF3
MeO
CF3
NO2
CN
2n
90%
2o
83%
H
9
10
11
12
32
2
H
Zn(OTf)2
TfOH
Ga(OTf)3
50
13
97 (91)[c]
0
MeO
Me
Ac
[a]
i
2p
70%
H
2q
81%
Conditions: 1a (0.25 mmol), PrOH (1.25 mmol), and
[b]
catalyst (5 mol%) in solvent (3 mL) at reflux for 12 h.
H
Determined by 1H NMR (400 MHz) analysis of the
unpurified reaction mixture using dibenzyl ether as the
[c]
internal standard.
isolated yield.
The value in parentheses is the
MeO
CONEt2
MeO
2r
2s
82%
68%
[a]
i
Conditions: 1 (0.25 mmol), PrOH (1.25 mmol), and
With the optimal conditions in hand, the substrate
scope of secondary benzylic alcohols 1 was
Ga(OTf)3 (5 mol%) in PhCF3 (3 mL) at reflux for 12 h.
[b]
[c]
Isolated yield is shown.
In DCE (3 mL) at reflux.
2
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10.1002/adsc.201801135
Advanced Synthesis & Catalysis
[d]
With 10 mol% Ga(OTf)3.
A mixed solvent of
chemoselectivity at the secondary benzylic alcohol,
although the primary benzylic alcohol was converted
to isopropyl ether (9). Thus, the present system can
PhCF3/DCE (2 mL/1 mL) was employed to solubilize the
substrate.
chemoselectively
reduce
sterically
hindered
secondary benzylic alcohols in the presence of
primary alcohols.
The present system was then applied to the direct
reduction of tertiary benzylic alcohols
4
to
triarylmethanes 5 (Table 3). It is important to note
that the significance of the triarylmethane motif in
dye chemistry, bioorganic chemistry, and material
science is well-known.[1e] A variety of tertiary
benzylic alcohols 4, undergo the direct reduction to
afford the corresponding products 5a–5g in 89–98%
yields, regardless of the electronic properties of the
aromatic ring. In contrast to the reactions of
secondary benzylic alcohols, these reactions complete
within 1 h, probably due to the high stability of the
triarylmethyl cation. Reduction-sensitive carbonyl
functionalities, such as ketone and aldehyde, are also
maintained during the reaction, and the hydroxy
group is selectively reduced to give 5h and 5i.
chemoselective
benzylic OH
reduction
i
OH
H
PrOH (5 equiv.)
Ga(OTf)3 (5 mol%)
Ph
Ph
DCE, reflux, 13 h
OH
aliphatic OH
OH
diol 6
7
78%
secondary
benzylic OH
chemoselective
reduction
i
OH
H
PrOH (10 equiv.)
Ga(OTf)3 (5 mol%)
Ph
Ph
PhCF3, reflux, 14.5 h
OiPr
OH
diol 8
primary
benzylic OH
9
69%
Table 3. Substrate scope of tertiary benzylic alcohols 4.[a]
Scheme 2. Chemoselective reduction of secondary
benzylic alcohol in the presence of primary alcohols.
iPrOH (5 equiv.)
OH
H
Ga(OTf)3 (5 mol%)
Ph
Ph
Ph
Ph
PhCF3, reflux, 1 h
Ar
Ar
To elucidate the reaction mechanism, a series of
control experiments was carried out (Scheme 3).
When the direct reduction of 1a was performed using
deuterium-labeled benzyl alcohol as a reductant, 99%
deuterium incorporation was observed at the benzylic
position of 2a-d. This result indicates that the
deuterium of benzyl alcohol was transferred to the in
situ-generated benzyl cation. Next, we performed the
direct reduction of 1a with isopropanol under gallium
catalysis and monitored the product distribution at
appropriate time intervals. The etherification of 1a
was quite rapid, and ether 3 was observed almost
exclusively in 0.25 h. However, as the reaction
proceeded, ether 3 gradually disappeared, and the
yield of 2a increased. In addition, we also confirmed
that ether 3 was converted to 2a under the standard
reaction conditions. These results demonstrate that
ether 3 is the intermediate leading to 2a, and the
hydride transfer process is rate-determining. On the
basis of these observations, a plausible mechanism is
proposed in Scheme 3, which is consistent with the
results given in Table 2, where the electron density of
the aromatic ring significantly affects the reaction
rate. Specifically, an electron-rich aromatic ring
confers a longer lifetime to the benzylic cation
intermediate, providing an opportunity for effective
hydride transfer. On the contrary, an electron-
deficient aromatic ring destabilizes the benzylic
cation, decreasing the opportunity for hydride transfer.
4
5
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
OMe
5a
98%[b]
5b
96%
5c
95%
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
F
Cl
Br
5d
89%[c]
5e
93%
5f
98%
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
CF3
Ac
CHO
5g
90%
5h
97%[c]
5i
84%[c,d]
[a]
i
Conditions: 4 (0.25 mmol), PrOH (1.25 mmol), and
Ga(OTf)3 (5 mol%) in PhCF3 (3 mL) at reflux for 1 h
Isolated yield is shown. [b] PhCF3 (4 mL) was employed to
[c]
[d]
solubilize the substrate.
Run for 2 h.
In DCE (3 mL) at reflux.
To further demonstrate the synthetic utility of this
method, chemoselective reduction was investigated
using diol 6 containing both a benzylic and an
aliphatic alcohol (Scheme 2). As anticipated, direct
reduction proceeded with complete chemoselectivity
at the benzylic alcohol, and the aliphatic alcohol
remained intact (7).[22] We also conducted the direct
reduction of diol 8 bearing both a secondary and a
primary benzylic alcohol.
reduction also proceeded
In this case, direct
with complete
3
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10.1002/adsc.201801135
Advanced Synthesis & Catalysis
resulting mixture was stirred in a pre-heated oil bath (105
˚C) for 12 h. The reaction mixture was cooled to room
temperature, diluted with Et2O, filtered through a short pad
of activated alumina, and concentrated under reduced
1. Deuterium labeling experiment
PhCD2OH (5 equiv.)
Ga(OTf)3 (5 mol%)
OH
D (99%)
PhCF3, reflux, 12 h
pressure.
The residue was purified by flash
Ph
Ph
Ph
Ph
chromatography on silica gel (hexane/EtOAc) to give the
corresponding product 2.
2a-d
46%
1a
D
Ph
O
d–
Ga(OTf)3
D
Ph d+ Ph
Acknowledgements
2. Monitoring of the product distribution
We are grateful to Prof. Shuji Akai (Osaka University) for his
kind and helpful discussions. We also thank Prof. Masayuki
Inoue (The University of Tokyo), Prof. Takeo Kawabata (Kyoto
University), Prof. Tomohiko Ohwada (The University of Tokyo),
Dr. Mitsuaki Ohtani (ITSUU Laboratory), and Dr. Kin-ichi
Tadano (ITSUU Laboratory) for helpful discussions.
i
PrOH (5 equiv.)
OiPr
Ph
OH
H
Ga(OTf)3 (5 mol%)
PhCF3, reflux
Ph
Ph
Ph
Ph
Ph
1a
2a
3
NMR yield [%]
Time [h]
Entry
2a
3
1
2
3
4
5
0.25
1
2
98
76
41
5
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In conclusion, We have developed a novel
Ga(OTf)3/isopropanol catalytic system for the direct
reduction of benzylic alcohols. The Ga(OTf)3-
assisted hydride transfer of the in situ-generated
benzylic isopropyl ethers is the key step of this
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Using our novel system,
chemoselective reduction of benzylic alcohols can be
achieved even in the presence of other alcohol
moieties. Furthermore, this method generates only
water and acetone as byproducts and thus provides an
atom-economic and environmentally benign approach
to the preparation of di- and triarylmethanes, which
are ubiquitous substructures in bioactive compounds
and functional materials.
Experimental Section
General procedure: In a glove box, Ga(OTf)3 (6.5 mg,
0.0125 mmol) was charged in an oven-dried vial equipped
with a stirring bar. Outside the glove box, to the vial was
added a solution of benzylic alcohol 1 (0.25 mmol) and
isopropanol (75.1 mg, 1.25 mmol) in PhCF3 (3 mL). The
4
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10.1002/adsc.201801135
Advanced Synthesis & Catalysis
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[15] We also examined other alcohols as the reductant.
The use of cyclohexanol and benzyl alcohol in the
direct reduction of 1a under gallium catalysis provided
5
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10.1002/adsc.201801135
Advanced Synthesis & Catalysis
2a in 47% and 43% yields, respectively. Thus,
isopropanol is the optimal reductant in terms of atom-
economy and reaction efficiency.
Ga(OTf)3 exhibits superior catalytic activity compared
with other metal triflates.
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yield) instead of 2a. This was likely due to the
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the decreased Lewis acidity or decomposition of the
catalyst.
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[19] The reaction of benzylic alcohols having highly
electron-rich aromatic rings afforded
a complex
mixture probably due to the intermolecular Friedel–
Crafts reaction.
[20] Treatment
of
1,3-diphenylpropan-1-ol
with
isopropanol under the standard conditions led to the
formation of (E)-1,3-diphenylpropene via dehydration.
[21] Longer reaction times and higher catalyst loadings
did not improve the yield.
[17] Although the possibility that TfOH produced from
Ga(OTf)3 and isopropanol or H2O is the actual catalyst
for the reaction cannot be ruled out, it is unclear why
[22] In PhCF3, isopropyl etherification of the aliphatic
hydroxy group in product 7 occurred to some extent.
6
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10.1002/adsc.201801135
Advanced Synthesis & Catalysis
COMMUNICATION
An Efficient Ga(OTf)3/Isopropanol Catalytic
System for Direct Reduction of Benzylic Alcohols
iPrOH
"
OH
H
cat. Ga(OTf)3
PhCF3, reflux
Ar1
Ar2
Ar1
Ar2
Adv. Synth. Catal. Year, Volume, Page – Page
benzylic alcohols
diarylmethanes
d–
Ga(OTf)3
H2O
byproduct
acetone
H
O
Masahiro Sai*
d+
Ar1
Ar2
hydride transfer
7
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