Direct Reduction of Allylic Alcohols Using Isopropanol as Reductant

Article abstract of DOI:10.1002/adsc.201800731

The lithium cation-catalyzed direct reduction of allylic alcohols to alkenes using isopropanol as a hydride donor was developed. The hydride transfer of the in situ-generated lithium isopropoxide to an allylic cation is the key process in this transformation. The reaction generates only water and acetone as byproducts, which highlights the synthetic utility of this method. (Figure presented.).

Full text of DOI:10.1002/adsc.201800731

Title: Direct Reduction of Allylic Alcohols Using Isopropanol as
Reductant
Authors: Masahiro Sai
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10.1002/adsc.201800731
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Direct Reduction of Allylic Alcohols Using Isopropanol as
Reductant
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######.
transition metal catalysts.[8] However, to the best of
Abstract. The lithium cation-catalyzed direct reduction of
allylic alcohols to alkenes using isopropanol as a hydride our knowledge, there have been no reports on the use
donor was developed. The hydride transfer of the in situ-
generated lithium isopropoxide to an allylic cation is the
key process in this transformation. The reaction generates
only water and acetone as byproducts, which highlights the
synthetic utility of this method.
of isopropanol as a reductant in the direct reduction
of alcohols to alkanes. In 2009, Zhou et al. reported
an iron-catalyzed direct reduction of allylic alcohols
using alcohols as the reductant.[6c] However, this
catalytic system required the use of benzyl alcohol,
which generated
a
stoichiometric amount of
Keywords: alcohols; lithium; reduction; hydride transfer;
allylic cations
benzaldehyde as the byproduct, and isopropanol
proved completely ineffective. In this paper, we
describe the lithium cation-catalyzed direct reduction
of allylic alcohols to alkenes using isopropanol as the
reductant (Scheme 1).
Alcohols are versatile synthetic precursors and can
participate in a variety of useful transformations.[1]
Among them, the deoxygenation of alcohols to
alkanes is a fundamental, but important reaction in
organic synthesis. However, due to the poor leaving
ability of the hydroxy group, alcohols are generally
converted into the corresponding halides or
pseudohalides prior to reduction,[2–4] which can be a
Meerwein–Ponndorf–Verley Reduction: (reduction of carbonyls to alcohols)
M
OH
O
OH
O
O
O
M
R
H
R
M
R
R
H
R
R
carbonyls
(excess)
alcohols
This Work: (direct reduction of alcohols to alkenes)
"
OH
H
Li+
"
Li
H
O
lengthy and wasteful process.
Therefore, the
Ar
Ar
Ar
Ar
OH
Ar
Ar
development of efficient catalytic systems for the
direct reduction of alcohols is highly desirable from
the synthetic and atom-economic points of view.[5,6]
In 2001, Baba et al. first developed a mild and
general reducing system using indium trichloride and
chlorodiphenylsilane.[5d] A variety of secondary and
tertiary alcohols were effectively reduced to the
corresponding alkanes in high yields. Since then,
several systems capable of such transformations have
been reported, but most utilize hydrosilanes as the
reductant.[5] In this context, we attempted to develop
a new catalytic system based on isopropanol as a
hydride source, because such a system would only
generate water and acetone as byproducts, and would
be mechanistically intriguing due to the successive
cleavage of C–O and C–H bonds. Isopropanol is a
well-known hydride donor in the Meerwein–
Ponndorf–Verley (MPV) reduction,[7] which utilizes a
reversible hydride transfer from isopropanol to a
carbonyl substrate activated by a Lewis acid. It is
also often employed in the transfer hydrogenation of
carbonyls and imines in combination with various
allylic alcohols
alkenes
hydride transfer
H2O
acetone
byproduct
Scheme 1. Direct reduction of allylic alcohols using a
LiPF6/isopropanol catalytic system.
We began our investigation with the direct
reduction of allylic alcohol 1a with isopropanol
(Table 1). To realize the reaction, we chose lithium
salts as catalysts, because the hardness of the lithium
cation as a Lewis acid should be suitable to enhance
the C–O bond cleavage of 1a, and the in situ-
generated lithium alkoxide should be nucleophilic
enough to induce the hydride transfer. In addition,
the use of lithium salts as Lewis acids is particularly
attractive in terms of earth abundance, low cost, and
nontoxicity.
When lithium hexafluorophosphate
(LiPF6) was used as the catalyst and isopropanol was
employed as the solvent, allylic isopropyl ether 3a
was formed exclusively instead of the desired product
2a (entry 1).[9]
This was likely due to the
1
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10.1002/adsc.201800731
Advanced Synthesis & Catalysis
coordination of isopropanol to the catalyst, leading to
the decreased Lewis acidity or decomposition of the
catalyst. Therefore, the reaction was performed with
10 equiv of isopropanol in 1,2-dichloroethane (DCE).
As a result, the direct reduction of 1a with
isopropanol proceeded in a moderate yield (entry 2).
The best result was obtained by employing 5 equiv of
isopropanol, giving 2a in 76% isolated yield, with
complete consumption of 1a and 3a (entry 3).[10]
Further decrease in the amount of isopropanol
resulted in a diminished yield of 2a, with a small
amount of enone 5 (entry 4). The use of benzyl
alcohol instead of isopropanol was also highly
effective for the reaction, providing 2a in 84 % yield,
although a stoichiometric amount of benzaldehyde
was generated as a byproduct (entry 5). With other
alcohols such as ethanol and methanol, allylic ethers
3 were mainly obtained (entries 6 and 7). After brief
screening of lithium salts, we found that LiBF4
showed comparable catalytic activity under the
optimized conditions (entry 8); however, the use of
LiOTf gave only isopropyl ether 3a (entry 9).
mildly electron-deficient aryl groups required a
longer reaction time (6 h) to achieve full conversion.
Table 2. Scope of allylic alcohols 1 bearing the same
substituents at the - and -positions.[a]
iPrOH (5 equiv.)
OH
H
LiPF6 (10 mol%)
DCE, reflux
Ar
Ar
Ar
Ar
1
2
H
Me
H
Me
Me
Me
2b
2c
78% (2 h)[b]
83% (2 h)[b]
H
H
MeO
OMe
F
F
2e
86% (2 h)
2d
55% (1 h)[b]
H
H
Cl
Cl
Br
Br
2f
2g
83% (6 h)
Table 1. Optimization of reaction conditions.[a]
86% (6 h)
[a]
i
Conditions: 1 (0.25 mmol), PrOH (1.25 mmol), and
ROH
LiPF6 (10 mol%)
OH
H
LiPF6 (10 mol%) in DCE (2.5 mL) at reflux. Isolated yield.
[b] LiOTf/PhCF3 at reflux used instead of LiPF6/DCE.
DCE, reflux, 1 h
Ph
Ph
Ph
Ph
1a
2a
OR
Ph
Ph
O
Next, the scope of allylic alcohols 6 bearing
different substituents at the - and -positions was
examined (Table 3). In such reactions, isomers 7 and
7’ were generated due to double-bond isomerization.
Thus, we investigated the electronic effects of the
,-aryl substituents on the isomeric ratio. First, the
electron density of one of the two aryl groups of 6
was increased. Direct reduction of (E)-1-phenyl-3-
(p-tolyl)prop-2-en-1-ol 6a, which contained a methyl
group on the aromatic ring at the -position, gave a
1:1.5 mixture of 7a and 7a’ in 66% combined yield
(the structure of the major product is shown in Table
Ph
Ph
Ph
O
Ph
Ph
Ph
ether 3
dimer 4
enone 5
Yield [%][b]
Entry ROH [equiv.]
2a
3
4
5
1
2
3
4
5
6
7
iPrOH[c]
0
55
>99 (3a)
41
0
0
0
0
0
12
9
0
0
0
iPrOH (10)
iPrOH (5)
iPrOH (2)
BnOH (5)
EtOH (5)
MeOH (5)
iPrOH (5)
iPrOH (5)
<1
<1
12
0
4
4
83 [76]
59
87 [84]
15
0
0
0
26 (3b)
35 (3c)
0
6
3).
A similar reaction of (E)-3-phenyl-1-(p-
8[d]
85 [75]
0
0
0
tolyl)prop-2-en-1-ol 6a’, the regioisomer of 6a,
showed the same regioselectivity (7a/7a’ = 1:1.5) and
yield (63%) as those of 6a.[12] These results indicate
that the reaction intermediates are little affected by
the structure of the substrates. Replacement of the
methyl group with a more electron-donating methoxy
or trimethyl substituent improved the isomeric ratio
to 2.4:1 (7d/7d’). Electron-deficient aryl substituents
also had a beneficial effect on the isomeric ratio.
Specifically, the reactions of substrates possessing
trifluoromethyl or nitro groups gave isomeric ratios
of 2.8:1 (7f/7f’) and 5.3:1 (7g/7g’), respectively,
although longer reaction times were required. These
results revealed that the isomeric ratio correlated with
the electronic properties of the aryl substituents of 6.
On the basis of these findings, we prepared various
substrates, with large differences in the electron
densities of the two aryl groups. Consequently,
substrate 6i, which had a methoxy-substituted aryl
ring at the -position and a nitro-substituted aryl ring
9[e]
>99 (3a)
[a]
Conditions: 1a (0.25 mmol), ROH, and LiPF6 (10
mol%) in DCE (2.5 mL) at reflux for 1 h.
[b]
Determined
1
by H NMR (400 MHz) analysis of the crude reaction
mixture. Isolated yield in bracket. [c] iPrOH (2.5 mL) was
employed as solvent instead of DCE. [d] LiBF4 (10 mol% )
[e]
was used as catalyst.
catalyst.
LiOTf (10 mol%) was used as
With these results in hand, the scope of allylic
alcohols 1 bearing the same substituents at the - and
-positions was first examined (Table 2). Allylic
alcohols containing electron-rich (1b–1d) and slightly
electron-deficient (1e) aryl groups smoothly
underwent the direct reduction to afford the
corresponding alkenes in 55–86% yields.[11] On the
other hand, the reactions of substrates 1f and 1g with
2
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10.1002/adsc.201800731
Advanced Synthesis & Catalysis
i
PrOH (5 equiv.)
at the -position, gave the best isomeric ratio of
13.3:1 (7i/7i’). In these reactions, the double bonds
formed near the electron-deficient aryl groups except
for 7d/7d’.[13] We also examined the direct reduction
of an alkyl-substituted allylic alcohol, but the reaction
resulted in the formation of the corresponding
diene.[14] Further expansion of substrate scope will be
the subject of future research.
OR
H
LiPF6 (10 mol%)
DCE, reflux, 1 h
Ph
Ph
Ph
Ph
3
2a
R = Me, 76%
R = Et, 75%
R = iPr, 73%
R = tBu, 74%
R = Ac, 73%
Scheme 2. Direct reduction of allylic ethers 3.
Table 3. Scope of allylic alcohols 6 bearing different
substituents at the - and -positions.[a,b]
In order to gain insight into the reaction
mechanism, a series of control experiments was
conducted (Scheme 3). First, the direct reduction of
1a was performed using deuterium-labeled benzyl
alcohol as the reductant. The reaction afforded 2a-d
containing a deuterium atom (93%) at the allylic
position, indicating that the deuterium at the benzylic
position was transferred. When enantioenriched
allylic alcohol (R)-1a (98% ee) was reacted under the
conditions at ambient temperature, isopropyl ether 3a
was obtained in racemic form, suggesting a
mechanism involving an allylic cation intermediate
during the etherification event. Treatment of 1a with
a 1:1 mixture of benzyl alcohol and the deuterated
counterpart led to the formation of a 4.3:1 ratio of 2a
and 2a-d, indicating that the hydride transfer process
was rate-determining and the cleavage of the C–O
bond in 1a readily occurred even at ambient
temperature. Second, 1a was treated with LiPF6 in
the absence of isopropanol, resulting in the
disproportionation[6c,15] of 1a to form 2a and 5 via the
formation of dimer 4. This event was supported by
the separate reaction of dimer 4 with LiPF6 under the
same conditions that formed a mixture of 2a and 5.
iPrOH (5 equiv.)
OH
H
H
LiPF6 (10 mol%)
DCE, reflux
Ar1
Ar2
Ar1
Ar2
Ar1
Ar2
g
a
6
7
7'
H
H
Ar1
Ar2
Ar1
Ar2
Me
MeO
66% (2 h)
61% (1 h)[c]
7a/7a' = 1:1.5
7b/7b' = 1:1.9
Me
Ar1
H
H
OMe
Ar1
H
Ar2
Ar1
Ar2
Ar2
Me
Me
F
55% (1 h)[c]
84% (1 h)
7d/7d' = 2.4:1
78% (2 h)
7e/7e'[d]
7c/7c' = 1:2.0
H
H
Ar1
Ar2
Ar1
84% (22 h)[e]
Ar2
F3C
O2N
74% (6 h)
7f/7f' = 2.8:1
7g/7g' = 5.3:1
H
H
Ar1
Ar2
Ar1
Ar2
F3C
OMe O2N
OMe
63% (2 h)[c]
52% (1 h)
7i/7i' = 13.3:1
7h/7h' = 5.7:1
[a]
i
Conditions: 6 (0.25 mmol), PrOH (1.25 mmol), and
LiPF6 (10 mol%) in DCE (2.5 mL) at reflux. Isolated
combined yield. The color of two aromatic moieties
exhibits the relationship between the substrates 6 and the
products 7 and 7’. [b] The ratio of 7 and 7’ was determined
by 1H NMR analysis (400 MHz) of the crude product. The
[c]
structure of the major product is shown.
at reflux used instead of LiPF6/DCE.
LiOTf/PhCF3
[d]
The ratio of 7e
and 7e’ cannot be identified by 1H NMR analysis. [e] With
20 mol% LiPF6.
The direct reduction of allylic ethers using alcohols
as the reductant is also largely unexplored. Therefore,
to further expand the substrate scope, the direct
reduction of allylic ethers was carried out under the
standard reaction conditions (Scheme 2). A variety
of allylic ethers 3 smoothly underwent the direct
reduction to afford 2a in 73–76% yields under the
same conditions as those of alcohols 6.
3
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10.1002/adsc.201800731
Advanced Synthesis & Catalysis
a) reaction mechanism
the carbon atom with a greater positive charge
preferentially gives alkene 7i in which the double
bond is located near the electron-deficient aryl
group.[13]
PhCD2OH (5 equiv.)
OH
D (93%)
LiPF6 (10 mol%)
DCE, reflux, 1 h
Ph
Ph
Ph
Ph
Ph
Ph
1a
2a-d, 60%
iPrOH (5 equiv.)
LiPF6 (10 mol%)
OiPr
On the basis of these results, a plausible
mechanism is proposed in Scheme 4. Initially, the
hydroxy group in 1a is activated by a lithium cation,
resulting in the formation of an allylic cation
intermediate, which is rapidly trapped by isopropanol
to afford isopropyl ether 3a. Then, hydride transfer
through a free allylic cation occurs to provide the
desired product 2a. The allylic cation intermediate
can also be captured by 1a, leading to dimer 4. While
4 can undergo hydride transfer to give 2a, 4 is more
rapidly transformed into 3a in the presence of excess
isopropanol.
OH
DCE, rt, 1 h
Ph
Ph
3a, 91%
racemate
(R)-1a
98% ee
PhCH2OH (2.5 equiv.)
PhCD2OH (2.5 equiv.)
LiPF6 (10 mol%)
OH
H
D
DCE, reflux, 1 h
Ph
Ph
Ph
Ph
Ph
Ph
1a
2a
2a-d
80% combined yield
2a/2a-d = 4.3:1
b) disproportionation (NMR yields)
OH
O
LiPF6 (5 mol%)
Ph
Ph
Ph
DCE, reflux, 1 h
Ph
Ph
Ph
1a
2a, 70%
5, 64%
LiPF6 (5 mol%)
DCE, reflux, 1 h
2a
55%
5
42%
Ph
Ph
OH
iPrOH (5 equiv.)
LiPF6 (10 mol%)
Ph
O
Ph
hydride transfer
rate-determining step
Ph
Ph
2a
76%
1a
4
DCE, reflux, 1 h
Li+
c) transition state
OH
Li
etherification
OH
iPrOH (5 equiv.)
LiPF6 (10 mol%)
H
O
OiPr
Ph
OiPr
major
Ph
Ph
DCE, rt, 1 h
H
Mes
Ph
Mes
Mes
Ph
Ph
H
O
free allylic cation
Ph
Ph
6d
8
8'
allylic cation
Ph
Ph
Ph
Ph
H2O
97% combined yield
LiPF6 (10 mol%)
DCE, reflux, 1 h
Li+
2a
LiOH
8/8' = 4:1
3a
H
O
Li+
1a
Li
Ph
Ph
H
H
O
H
major
six-membered
transition state
Ph
Ph
Mes
Ph
Mes
Mes
Ph
sterically
favored
disproportionation
7d
7d'
Ph
O
dimer 4
H2O
Ph
31% combined yield
7d/7d' = 1.9:1
O
Li+
free allylic cation
Ph
Ph
5
H
Li
O
electronically
favored
H
d+
Scheme 4. Plausible mechanism.
O2N
OMe
7i
major
O2N
OMe
free allylic cation
from 6i
(7i/7i' = 13.3:1, see Table 3)
In conclusion, we developed a novel lithium
cation-catalyzed direct reduction method of allylic
alcohols using isopropanol as the reductant. The
hydride transfer of the in situ-generated allylic
isopropyl ethers via a free allylic cation is the key
process in this transformation. The direct reduction
of allylic alcohols is catalyzed by an alkali metal and
generates only water and acetone as byproducts,
which demonstrates the synthetic utility of the
developed methodology.
Scheme 3. Control experiments.
On the other hand, in the presence of excess
isopropanol, dimer 4 was efficiently transformed into
3a followed by a hydride transfer to yield 2a. Next,
to investigate whether the hydride transfer process
involved a free allylic cation or a six-membered
transition state, 6d was subjected to the reaction
conditions at ambient temperature. Allylic alcohol
6d smoothly underwent etherification to afford a 4:1
mixture of isopropyl ethers 8 and 8’.[16] The
following hydride transfer of the mixture provided
alkenes 7d and 7d’ in a ratio of 1.9:1, which did not
reflect the ratio of the ether intermediates. This
experimental outcome is inconsistent with a pathway
involving a six-membered transition state,[17] and
supports a free allylic cation mechanism. In the case
of 6d, the hydride transfer occurs at the sterically
less-hindered carbon atom of the allylic cation to give
7d as a major product.[18] This mechanism is also in
agreement with the selectivity observed in the direct
reduction of allylic alcohols bearing two
electronically different aryl groups. For example, in
the case of 6i, the nucleophilic attack of hydride to
Experimental Section
An oven-dried test tube was charged with LiPF6 (3.8 mg,
0.025 mmol) and a stirrer bar in an Ar-filled glovebox.
Outside the glovebox, to the tube was added a solution of
allylic alcohol 1 (0.25 mmol) and isopropanol (75.1 mg,
1.25 mmol) in DCE (2.5 mL). The mixture was then
stirred in a pre-heated oil bath (reflux) for 1 h. The
mixture was cooled to room temperature, diluted with Et2O
(5 mL), and filtered through a short alumina column,
eluting with additional Et2O (10 mL). The filtrate was
concentrated and purified by column chromatography on
silica gel (hexane/EtOAc) to give the corresponding
product 2.
Acknowledgements
4
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10.1002/adsc.201800731
Advanced Synthesis & Catalysis
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.
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Catal. 2015, 357, 3115–3120.
[4] For a review on the reduction of alcohols, see: J. M.
Herrmann, B. König, Eur. J. Org. Chem. 2013, 7017–
7027.
[5] For selected examples of the direct reduction of
alcohols using hydrosilanes, see: a) V. Gevorgyan, J.-X.
Liu, M. Rubin, S. Benson, Y. Yamamoto, Tetrahedron
Lett. 1999, 40, 8919–8922; b) T. Miyai, M. Ueba, A.
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[10] It is important to note that 3a is the intermediate
leading to 2a, which is clearly demonstrated in Scheme
2.
[11] Further optimization of reaction conditions revealed
that LiOTf/PhCF3 system was superior than LiPF6/DCE
for the direct reduction of allylic alcohols with
electron-rich aryl groups.
[12] The reaction of allylic alcohol 6a’ showed the same
regioselectivity and yield as those of 6a.
[6] For selected examples of the direct reduction of
alcohols using other hydride sources, see: a) T.
Funabiki, Y. Yamazaki, K. Tarama, J. Chem. Soc.,
Chem. Commun. 1978, 63–65; b) A. G. Myers, M.
5
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10.1002/adsc.201800731
Advanced Synthesis & Catalysis
H
[16] The structure and ratio of 8 and 8’ were determined
by 1H NMR and NOE studies (see the Supporting
Information).
iPrOH (5 equiv.)
LiPF6 (10 mol%)
OH
7a
H
Me
Me
g
a
[17] If the hydride transfer involves a six-membered
transition state, the ratio of intermediates 8 and 8’
would be reflected in that of the resulting alkenes 7d
and 7d’.
DCE, reflux, 2 h
Me
6a'
7a'
63% combined yield
7a/7a' = 1:1.5
hydride shift
Li+
OiPr
Ph
H
H
O
[13] DFT calculations of electronic characteristics of
allylic cations, see: A. N. Kazakova, R. O. Iakovenko, I.
A. Boyarskaya, V. G. Nenajdenko, A. V. Vasilyev, J.
Org. Chem. 2015, 80, 9506–9517.
Mes
Ph
Mes
Mes
Ph
8
7d'
major
six-membered
transition state
major
[18] The change of alcohols to probe steric effects
displayed no regular trends in the selectivity of 7d and
7d’.
[14] The reaction of alkyl-substituted allylic alcohol 9
furnished diene 10 instead of the desired reduced
product.
ROH (5 equiv.)
LiPF6 (10 mol%)
OH
H
H
i
PrOH (5 equiv.)
OH
LiPF6 (10 mol%)
DCE, reflux, 1 h
Mes
Ph
Mes
Ph
Mes
Ph
Ph
DCE, reflux, 1 h
Ph
6d
7d
7d'
9
10, 77%
E,E/E,Z = 1.9:1
OH
OH
OH
OH
[15] a) Z. Zhu, J. H. Espenson, J. Org. Chem. 1996, 61,
324–328; b) P. N. Chatterjee, S. Roy, Tetrahedron
2012, 68, 3776–3785; c) C.-K. Chan, Y.-L. Tsai, M.-Y.
Chang, Tetrahedron 2017, 73, 3368–3376.
Ph
84%
7d/7d' = 2.4:1
60%
7d/7d' = 2.9:1
66%
7d/7d' = 2.7:1
89%
7d/7d' = 2.2:1
6
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10.1002/adsc.201800731
Advanced Synthesis & Catalysis
COMMUNICATION
Direct Reduction of Allylic Alcohols Using
Isopropanol as Reductant
OH
Li+
"
Adv. Synth. Catal. Year, Volume, Page – Page
"
OH
H
Li
H
O
Ar
Ar
Ar
Ar
Ar
Ar
Masahiro Sai*
7
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