Erbium-Catalyzed Regioselective Isomerization-Cobalt-Catalyzed Transfer Hydrogenation Sequence for the Synthesis of Anti-Markovnikov Alcohols from Epoxides under Mild Conditions

Article abstract of DOI:10.1021/acscatal.0c03294

Herein, we report an efficient isomerization-transfer hydrogenation reaction sequence based on a cobalt pincer catalyst (1 mol %), which allows the synthesis of a series of anti-Markovnikov alcohols from terminal and internal epoxides under mild reaction conditions (≤55 °C, 8 h) at low catalyst loading. The reaction proceeds by Lewis acid (3 mol % Er(OTf)3)-catalyzed epoxide isomerization and subsequent cobalt-catalyzed transfer hydrogenation using ammonia borane as the hydrogen source. The general applicability of this methodology is highlighted by the synthesis of 43 alcohols from epoxides. A variety of terminal (23 examples) and 1,2-disubstituted internal epoxides (14 examples) bearing different functional groups are converted to the desired anti-Markovnikov alcohols in excellent selectivity and yields of up to 98%. For selected examples, it is shown that the reaction can be performed on a preparative scale up to 50 mmol. Notably, the isomerization step proceeds via the most stable carbocation. Thus, the regiochemistry is controlled by stereoelectronic effects. As a result, in some cases, rearrangement of the carbon framework is observed when tri-and tetra-substituted epoxides (6 examples) are converted. A variety of functional groups are tolerated under the reaction conditions even though aldehydes and ketones are also reduced to the respective alcohols under the reaction conditions. Mechanistic studies and control experiments were used to investigate the role of the Lewis acid in the reaction. Besides acting as the catalyst for the epoxide isomerization, the Lewis acid was found to facilitate the dehydrogenation of the hydrogen donor, which enhances the rate of the transfer hydrogenation step. These experiments additionally indicate the direct transfer of hydrogen from the amine borane in the reduction step.

Full text of DOI:10.1021/acscatal.0c03294

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Research Article
Erbium-Catalyzed Regioselective Isomerization−Cobalt-Catalyzed
Transfer Hydrogenation Sequence for the Synthesis of Anti-
Markovnikov Alcohols from Epoxides under Mild Conditions
̈
Xin Liu, Lars Longwitz, Brian Spiegelberg, Jan Tonjes, Torsten Beweries, and Thomas Werner*
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ABSTRACT: Herein, we report an efficient isomerization−transfer hydrogenation reaction sequence based on a cobalt pincer
catalyst (1 mol %), which allows the synthesis of a series of anti-Markovnikov alcohols from terminal and internal epoxides under
mild reaction conditions (≤55 °C, 8 h) at low catalyst loading. The reaction proceeds by Lewis acid (3 mol % Er(OTf)3)-catalyzed
epoxide isomerization and subsequent cobalt-catalyzed transfer hydrogenation using ammonia borane as the hydrogen source. The
general applicability of this methodology is highlighted by the synthesis of 43 alcohols from epoxides. A variety of terminal (23
examples) and 1,2-disubstituted internal epoxides (14 examples) bearing different functional groups are converted to the desired
anti-Markovnikov alcohols in excellent selectivity and yields of up to 98%. For selected examples, it is shown that the reaction can be
performed on a preparative scale up to 50 mmol. Notably, the isomerization step proceeds via the most stable carbocation. Thus, the
regiochemistry is controlled by stereoelectronic effects. As a result, in some cases, rearrangement of the carbon framework is
observed when tri- and tetra-substituted epoxides (6 examples) are converted. A variety of functional groups are tolerated under the
reaction conditions even though aldehydes and ketones are also reduced to the respective alcohols under the reaction conditions.
Mechanistic studies and control experiments were used to investigate the role of the Lewis acid in the reaction. Besides acting as the
catalyst for the epoxide isomerization, the Lewis acid was found to facilitate the dehydrogenation of the hydrogen donor, which
enhances the rate of the transfer hydrogenation step. These experiments additionally indicate the direct transfer of hydrogen from
the amine borane in the reduction step.
KEYWORDS: epoxides, cobalt, transfer hydrogenation, alcohols, anti-Markovnikov
methods, the reductive opening of epoxides has recently
lcohols are important building blocks in organic
Achemistry and have a wide variety of applications as emerged as a powerful alternative strategy (Scheme 1B).13−15
pharmaceuticals, agrochemicals, solvents, or fragrances.1 The
The three major challenges in this transformation are the
control of the regioselectivity of the epoxide opening,
inhibition of the formation of allylic alcohols, and reduction
of substituted epoxides.
In previous studies, the reduction of alkyl epoxides using
classic heterogeneous reduction catalysts such as Pd/C usually
gave the respective alcohols with Markovnikov selectivity.16−18
The use of homogeneous catalysts for the (transfer) hydro-
direct synthesis from olefins by formal hydration of the
carbon−carbon double bond is a common synthetic pathway
both for the production of bulk and specialty chemicals.2 In
accordance with Markovnikov’s rule, the hydroxyl group is
generated at the most substituted carbon atom in most of these
processes. The direct hydration of olefins to anti-Markovnikov
alcohols is a long standing challenge in catalysis and only rarely
reported.3−5 The access to alcohols with an anti-Markovnikov
selectivity requires different strategies (Scheme 1). In industry,
olefins are often converted to anti-Markovnikov alcohols in a
homologation reaction by hydroformylation and subsequent
reduction (Scheme 1A).6−10 For lab-scale applications, a
hydroboration/oxidation sequence is often used to synthesize
anti-Markovnikov alcohols.11,12 Besides these well-established
Received: July 28, 2020
Revised: September 29, 2020
https://dx.doi.org/10.1021/acscatal.0c03294
© XXXX American Chemical Society
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Scheme 1. Synthetic Pathways Toward anti-Markovnikov
Alcohols and Current Challenges
Table 1. Catalyst Screening and Parameter Optimization for
the Cobalt-Catalyzed Transfer Hydrogenation of Epoxides
a
entry
catalyst
additive
solvent
conv./%
2a/%
c
1
2
3
4
5
6
7
8
Co-I
Co-II
AlCl3
AlCl3
AlCl3
AlCl3
LiOTf
InCl3
TfOH
Zn(OTf)2
Er(OTf)3
Er(OTf)3
Er(OTf)3
Er(OTf)3
Er(OTf)3
THF
THF
THF
THF
THF
THF
THF
THF
82
73
66
85
49
43
52
>99
>99
60
36
75
41
62
51
0
74
c
d
Co-III
Co-IV
Co-IV
Co-IV
Co-IV
Co-IV
Co-IV
Co-IV
Co-IV
Co-IV
Co-IV
c
43
39
47
c
80
9
THF
95
52
33
71
38
10
11
12
toluene
CH2Cl2
n-hexane
THF
b
13
a
Reaction conditions: 1a (0.50 mmol, 1.0 equiv), catalyst (1.0 mol
%), additive (3.0 mol %), NH3BH3 (0.60 mmol, 1.2 equiv), solvent
(1.5 mL), 45 °C, 8 h. The yield was determined by GC using
b
c
mesitylene as the internal standard. T = 23 °C, t = 24 h. The
Markovnikov alcohol (1-phenylethanol) was detected as the side
product. Acetophenone and 2-phenylacetaldehyde were formed.
d
genation or hydrosilylation reaction of epoxides has been
widely investigated.13,19−25 However, in these cases, typically
catalysts based on precious metals are employed, and often
only moderate selectivity toward the anti-Markovnikov
products is achieved. Most recently, Beller and co-workers
reported the selective hydrogenation of epoxides catalyzed by
an iron-triphos and cobalt−tetraphos complex in the presence
of Lewis and Brønsted acidic additives.14,26 However, high
catalyst loadings and drastic reactions conditions, e.g., high
for the transfer hydrogenation of alkynes using ammonia
borane as the hydrogen source.36 Initially, we performed the
conversion of 1a in the presence of 3.0 mol % of AlCl3 as the
Lewis acidic additive and ammonia borane as the hydrogen
donor. The cobalt pincer complex Co-IV was found to be the
most efficient catalyst. At a catalyst loading of only 1.0 mol %,
the anti-Markovnikov alcohol 2a was obtained in 74% yield
after 8 h at 45 °C (Table 1, entry 4). We compared the
performance of the phenyl-substituted PNP−pincer complex
Co-IV to other earth abundant metal catalysts under these
conditions.38 Notably, iron or manganese PNP complexes gave
only phenylacetaldehyde as the main product. Other hydrogen
donors such as alcohols or molecular hydrogen were found to
cause side reactions.38 Beside AlCl3, we also evaluated different
Lewis acids (LAs) and a Brønsted acid as additives for the
isomerization of 1a (entries 5−9).39,40 The use of InCl3, LiOTf
or trifluoromethanesulfonic acid (TfOH) led to significantly
lower yields of <50% for the desired product 2a (entries 5−7).
An improved yield of 80% was achieved when Zn(OTf)2 was
used as an additive (entry 8). However, erbium triflate which
has previously been reported as a catalyst for the isomerization
of epoxides39 proved to be the most efficient additive leading
to 2a in an excellent yield of 95% (entry 9). We also
considered other solvents which are commonly used in transfer
hydrogenation reactions such as toluene, CH2Cl2, or n-hexane
(entries 10−12). However, in these solvents, lower yields of
52, 33, and 71% were obtained, respectively. Remarkably, the
reaction could be carried out even at room temperature, and a
yield of 38% was obtained after 24 h (entry 13).
hydrogen pressures are required. A different approach for
15
̈
epoxide reduction was reported by Gansauer and Norton.
A
cooperative catalyst system based on Ti/Cr was used for the
radical reduction of epoxides at relatively low hydrogen
pressures, although high catalyst loadings and long reaction
times had to be employed. Notably, the allylic alcohol was
detected as a by-product when internal epoxides were used as
substrates. Due to our general interest in the use of catalysts
based on non-precious metals,27,28 we report here an efficient
isomerization−transfer hydrogenation reaction sequence based
on a cobalt pincer catalyst which allows the synthesis of anti-
Markovnikov alcohols from terminal and internal epoxides
under mild reaction conditions (Scheme 1C). The use of
transfer hydrogenation reagents instead of molecular hydrogen
has the advantage that high pressure equipment can be
avoided, and often, new and interesting reactivities arise.29,30
Ammonia borane is an attractive alternative to commonly used
hydrogen transfer agents such as alcohols since it is nonvolatile
and harmless.31−35
We started our study by investigating the catalytic activities
of a series of well-known cobalt complexes36,37 in the transfer
hydrogenation of styrene oxide (1a) (Table 1, entries 1−4).
Notably, Co-I has been reported by the groups of Luo and Liu
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With the optimal reaction conditions in hand, we explored
the scope of the Co-IV-based system on the isomerization−
transfer hydrogenation of different terminal epoxides 1 to yield
the corresponding anti-Markovnikov alcohols 2 (Table 2). The
A diglycidyl ether (1q) to diol 2q which was obtained in 73%
yield. Additionally, we could prove that also 1,1-disubstituted
epoxides are suitable substrates. A series of these compounds
1r−1w were converted, and the anti-Markovnikov alcohols
2r−2w were obtained in yields up to 89%.
One drawback of the previously reported iron-based
catalytic system was the limitation to the conversion of
terminal epoxides.14 The main reason for this is probably that
in the case of internal epoxides, the epoxide will isomerize to
the respective ketone, which is significantly harder to reduce.42
This prompted us to study the conversion of 1,2-disubstiuted
epoxides 3 (Table 3) and tri- and tetra-substituted epoxides 5
Table 2. Scope for the Synthesis of Anti-Markovnikov
a
Alcohols from Terminal Epoxides
Table 3. Scope for the Conversion 1,2-Disubstituted
Epoxides in the Isomerization−Cobalt-Catalyzed Transfer
a
Hydrogenation Sequence
a
Reaction conditions: 1a−w (0.50 mmol, 1.0 equiv), Co-IV (1.0 mol
%), Er(OTf)3 (3.0 mol %), NH3BH3 (0.60 mmol, 1.2 equiv), THF
(1.5 mL), 45 °C, 8 h. Isolated yields are given. The yield was
determined by GC using mesitylene as the internal standard. The
yield was determined by H NMR using mesitylene as the internal
standard. The amount of NH3BH3 was 2.0 equiv, and the reaction
b
c
1
d
time was 16 h.
a
Reaction conditions: 3a−l (0.50 mmol, 1.0 equiv), Co-IV (1.0 mol
%), Er(OTf)3 (3.0 mol %), NH3BH3 (0.60 mmol, 1.2 equiv), THF
(1.5 mL), 55 °C, 8 h. Isolated yields are given. The yield was
determined by GC using mesitylene as the internal standard. The
initial isomerization of the epoxide proceeds via the most
stable carbocation followed by a [1,2]-hydride shift to yield the
corresponding aldehyde as an intermediate.39,41 Subsequently,
the aldehyde is hydrogenated to the corresponding alcohol.
Thus, aryl substituted epoxides 1a−f were regioselectively
converted to the desired anti-Markovnikov alcohols 2a−f with
yields up to 95%. We turned our attention to alkyl-substituted
epoxides 1g and 1h. The conversion of these substrates is of
particular interest since the reaction of alkyl-substituted
epoxides, for example, hexene oxide (1g), usually leads to a
mixture of regioisomers using classical hydrogenation cata-
lysts.15−19 However, under our standard reaction conditions,
alcohols 2g and 2h were successfully obtained with anti-
Markovnikov selectivity. Notably, various functional groups are
tolerated under the reaction conditions, and epoxides bearing
different functionalities such as a siloxane group 1j, additional
hydroxyl 1k, alkenyl 1l, perfluoroalkyl 1m, tosyl 1n, or a
morpholine-substituted epoxide 1o were converted to the
respective alcohols 2j−o in good to excellent yields up to 87%.
Also, bisepoxides were successfully converted to the respective
diols, and the effectiveness of the methodology was
demonstrated at 10 mmol scale in the conversion of bisphenol
b
c
amount of NH3BH3 was 2.0 equiv, and the reaction time was 16 h.
The product was obtained as a mixture of two regioisomers.
d
(Table 4). In the case of epoxides 3, the isomerization occurs
via the most stable carbocation again followed by a 1,2-hydride
shift to afford the respective ketone which is subsequently
reduced to the corresponding alcohol 4.39,40 Notably, in the
presence of cobalt complex Co-IV at slightly elevated
temperature of 55 °C, it was possible to convert β-
methylstyrene oxide (3a) into 1-phenylpropan-2-ol (4a) in
an isolated yield of 93%. Other β-substituted styrene oxide
derivatives 3b and 3c bearing an alcohol or ester moiety were
converted to the respective products 4b and 4c in yields up to
65%. Cyclic starting materials with different secondary ring
sizes 3d−j were accepted as substrates, and the alcohols 4d−j
were obtained in yields up to 92%. Also, heterocyclic substrates
such as sulfone derivative 3k and an epoxidized Boc-protected
pyrrolidine 3l were converted leading to the desired alcohols
4k and 4l in 75 and 63% yield, respectively. Dicyclopentadiene
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Furthermore, we evaluated the conversion of even more
challenging tri- and tetra-substiuted epoxides (Table 4). Tri-
substituted substrates 5a−c were converted to the correspond-
ing anti-Markovnikov alcohols 6a−c in yields up to 89%.
Cedrene oxide (5d) was also successfully converted, and the
corresponding alcohol 6d was isolated in 81% yield. However,
the initial stereochemical information is lost at both stereo-
centers of the epoxides (at the first stereocenter due to the
formation of the higher substituted carbocation and at the
second stereocenter due to the formation of the ketone
intermediate). Notably, when α-pinene oxide (5e) was used as
the substrate 2,2,3-trimethyl-3-cyclopentene-1-ethanol (6e)
was obtained as the product. This can be explained by LA-
catalyzed rearrangement of 5e to form campholenic aldehyde
as an intermediate which is subsequently reduced to 6e.38,43
Also, tetramethylethylene oxide (5f) could be converted. In
this case, the epoxide opening initiates a Wagner−Meerwein
rearrangement which is followed by a 1,2-hydride shift to yield
3,3-dimethyl-2-butanone as an intermediate. The subsequent
Co-IV catalyzed transfer hydrogenation leads to 3,3-
dimethylbutan-2-ol (6f) in 56%.
Table 4. Scope and Limitation for the Conversion of Tri-
and Tetra-substituted Epoxides
a
We further evaluated the efficiency of the Co-IV system by
comparing it to classical hydrogenation catalysts and Beller’s
reported catalytic systems in the presence of molecular
hydrogen for the conversion of the terminal epoxide 1a (45
°C, 8 h) and the internal epoxide 3a (55 °C, 8 h). Under our
standard reaction conditions, we obtained 2a and 4a in 95%
and 93% yield, respectively (Table 5, entry 1). In contrast, the
use of previously reported Fe-tetraphos catalyst in combination
with trifluoroacetic acid (TFA) gave 2a and 4a in lower yields
of 63% and <5%, respectively (Table 5, entry 2).
The use of recently reported Co-triphos system in
combination with Zn(OTf)2 as isomerization catalyst led to
slightly increased yields of 78% for 2a and 62% for 4a (entry
3). Subsequently, we repeated both reactions using Er(OTf)3
as additive to catalyze the isomerization (entries 4 and 5).
Even though this led to a general improvement in the yields for
2a and 4a, the Co-IV system still gave the best results. This
clearly demonstrates not only the superiority of Er(OTf)3 as
the isomerization catalyst but also the higher efficiency of
catalyst Co-IV. The traditional hydrogenation catalysts Pd/C,
PtO2 and the Wilkinson catalyst gave 2a only in low yields of
<15% usually as a mixture of the Markovnikov and anti-
Markovnikov product (entries 6−8). Notably, the conversion
of internal epoxide 3a to the desired anti-Markovnikov product
4a was unsuccessful in the presence of these catalysts.
a
Reaction conditions: 5a−f (0.50 mmol, 1.0 equiv), Co-IV (1.0 mol
%), Er(OTf)3 (3.0 mol %), NH3BH3 (0.60 mmol, 1.2 equiv), THF
b
(1.5 mL), 55 °C, 8 h. Isolated yields are given. The yield was
c
determined by GC using mesitylene as the internal standard. dr =
4:1. The product was obtained as a mixture of diastereoisomers.38
d
dioxide (3m) was converted to the respective diol 4m in a
good yield of 83%. Epoxidized methyl oleate (3n) gave the
desired alcohol 4n in 57% yield as a mixture of two possible
regioisomers.
Having established the use of the Co-IV as an efficient
method for the synthesis of anti-Markovnikov alcohols from
epoxides, we further studied the scalability of this method
(Scheme 2).
Thus, we converted terminal epoxide 1a and 1,1- and 1,2-
disubsituted substrates 1r and 3a on a multi gram scale under
our standard reaction conditions and obtained the correspond-
ing products yields up to 85%.
Finally, we performed a detailed mechanistic investigation to
get a better insight into the mechanism of this reaction
sequence. Therefore, we monitored the conversion of the
model substrate 1a under the standard reaction conditions
(Figure 1A).
a
Scheme 2. Upscaling Studies
The epoxide 1a is initially isomerized to the aldehyde 7a
which is subsequently hydrogenated to yield the alcohol 2a.
After 15 min, > 60% of the starting material was already
converted to 7a (50%) and the final product 2a (13%). Several
control experiments were performed (Figure 1B). In the
absence of the catalyst Co-IV or ammonia borane, the epoxide
1a was fully converted (entry 2 and 3). Notably, the
isomerization product 7a was the only observed product.
This was also the dominant product when molecular hydrogen
was used instead of ammonia borane (entry 4). In the absence
of Er(OTf)3, no conversion of the starting material 1a was
detected (entry 5). This supports the proposed two-step
a
Reaction conditions: epoxide (50 mmol, 1.0 equiv), Co-IV (1.0 mol
%), Er(OTf)3 (3.0 mol %), NH3BH3 (1.2 equiv), THF (80 mL), 45
°C. 55 °C, 14 h. Isolated yields are given.
b
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Table 5. Hydrogenation of Terminal Epoxide 1a and Internal Epoxide 3a with H2 in the Presence of Known Catalysts under
a
Our Reaction Condition
b
c
entry
catalyst (mol %)
Co-IV (1.0)
Fe(BF4)·H2O (2.0), tetraphos (2.0)
Co(NTf2)2 (3.0), triphos (6.0)
Fe(BF4)·H2O (2.0), tetraphos (2.0)
Co(NTf2)2 (3.0), triphos (6.0)
Pd/C (10)
additive (mol %) hydrogen source
solvent
conv. 1a/% yield 2a/% conv 3a/% yield 4a/%
d
1
2
3
4
5
6
7
8
Er(OTf)3 (3.0)
TFA (2.0)
NH3BH3
THF
THF
THF
THF
>99
>99
>99
>99
>99
20
95
63
78
71
>99
6
>99
>99
>99
15
93
<5
62
36
67
(5)
-
H2 (20 bar)
H2 (40 bar)
H2 (20 bar)
H2 (40 bar)
H2 (20 bar)
H2 (20 bar)
H2 (20 bar)
Zn(OTf)2 (7.0)
Er(OTf)3 (3.0)
Er(OTf)3 (3.0)
THF
85
e
e
e
toluene
toluene
THF
8 (6)
4 (5)
1 (8)
PtO2 (10)
Rh(PPh3)3Cl (10)
15
16
10
6
-
a
b
c
d
The yield was determined by GC using mesitylene as the internal standard. T = 45 °C, t = 8 h. T = 55 °C, t = 8 h. NH3BH3 (0.6 mmol, 1.2
e
equiv). The yield of the Markovnikov alcohol product is given in brackets.
Additionally, we performed the reaction monitoring and the
control experiments with β-methylstyrene oxide (3a) as the
model substrate for 1,2-disubstituted epoxides (Figure 2).
Also, in this case, the epoxide 3a is initially isomerized, and
ketone 8a is obtained which is subsequently hydrogenated to
Figure 1. Kinetic profile (A) and control experiments (B) for the
conversion of styrene oxide (1a). aReaction conditions: 1a (0.5
mmol), Co-IV (1 mol %), Er(OTf)3 (3 mol %), NH3BH3 (1.2 equiv),
THF (1.5 mL), 45 °C, 8 h. The conversion and yields were
b
determined by GC using mesitylene as the internal standard. H2 (1
bar), NH3BH3 (1.0 mol %).
Figure 2. Kinetic profile (A) and control experiments (B) for the
a
conversion of β-methylstyrene oxide (3a). Reaction conditions: 3a
(0.5 mmol), Co-IV (1.0 mol %), Er(OTf)3 (3.0 mol %), NH3BH3
(1.2 equiv), THF (1.5 mL), 55 °C, 8 h. The conversion and yields
were determined by GC using mesitylene as the internal standard. bH2
(1 bar), NH3BH3 (1.0 mol %).
reaction sequence which proceeds via (1) an initial Er(OTf)3-
catalyzed isomerization of the starting material 1a to the
aldehyde 7a followed by (2) the Co-catalyzed transfer
hydrogenation of 7a to the anti-Markovnikov alcohol 2a.
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yield the alcohol 4a (Figure 2A). After 15 min, 49% of the
starting material was converted and 40% of 8a and 9% of the
final product 4a formed. As mentioned above, the initial
epoxide opening and isomerization proceeds via the more
stable benzylic carbocation which explains the regiochemistry
of the final product 4a. Similar results were also obtained in the
control experiments (Figure 2B). Full conversion of 3a was
achieved in the absence of the catalyst Co-IV or ammonia
borane, yielding the 8a as the only product (entry 2 and 3).
When molecular hydrogen was used instead of ammonia
borane 8a was also the main product (entry 4). As for the
conversion of terminal expoxide 1a, no reaction of 3a was
observed in the absence of Er(OTf)3 (entry 5). These
experiments additionally support the proposed two-step
reaction sequence.
These results prompted us to study both the isomerization
and the reduction of the intermediate in more detail. Thus, we
investigated the impact of selected LAs on the isomerization
step of the reaction sequence at 45 °C (Figure 3). In the
Figure 4. Study on the reduction of the isomerization products 7a
(A) and 8a (B) under different conditions.
solvent, the corresponding hydroboration products were
obtained as the main products. Thus, as expected, in the
absence of both Co-IV and Er(OTf)3, the hydroboration
product 11a was obtained in 85% after 3 h at 45 °C.
Interestingly, if only Er(OTf)3 is omitted, 2a is obtained as the
major product in 69%, while the boronic acid ester 11a is
formed as a side product in 13% yield. In the absence of Co-
IV, only the hydroboration product 11a was obtained in 31%
yield. We performed the same set of experiments for the
reduction of ketone 8a (Figure 4B). Also in this case, the
hydroboration product 12a was obtained in 74% yield in the
absence of Co-IV and Er(OTf)3. In the presence of Co-IV
alcohol, 3a was obtained as the major product in 72%, while
the yield for 12a dropped to 9%. Under the respective standard
reaction conditions used before for terminal and internal
epoxides 1 and 3, no conversion was observed when boronic
acid esters 11a and 12a were employed as substrates. This
clearly indicates that the reaction of epoxides does not proceed
via the respective boronic acid esters as intermediates under
our standard conditions.
Figure 3. Study on the isomerization of terminal epoxide 1a (A) and
internal epoxide 3a (B) in the presence of different LAs.a aReaction
conditions: 1a (0.5 mmol), additive (3 mol %), THF (1.5 mL), 45 °C
8 h. The reaction temperature was 45 °C for substrate 3a.
bPolymerization upon addition of B(C6F5)3.
Obviously, the erbium salt is not only necessary for the
isomerization of the epoxide to the corresponding aldehyde or
ketone but also for the suppression of the formation of side
products and enhancement of the reaction rate of the
reduction step. LAs are known to facilitate hydrogenation
and dehydrogenation reactions using pincer catalysts.45−47
They have also been studied as catalysts for the dehydrogen-
ation of ammonia borane.48 Moreover, cobalt and other non-
noble metal pincer systems were reported to catalyze the
dehydrocoupling of amine boranes.49,50 The latter has been
used as hydrogen source in transfer hydrogenation reaction
before.36,51 The herein-used Co catalysts were found to readily
dehydropolymerize methylamine borane under LA free
conditions.52 Thus, the influence of Er(OTf)3 on the reduction
step was further investigated. As mentioned above, the
conversion of 1a gave the desired product 2a in 95% yield
under our standard reaction conditions and in 38% after 24 h
at 23 °C, respectively (Table 1, entries 9 and 13). However, at
23 and 45 °C, the Co-IV catalyzed dehydrogenation of
ammonia borane seemed to be neglectable.38 Notably, in the
presence of 3.0 mol % Er(OTf)3, a conversion 94% of 1a was
observed after 1 h (Figure 3A), which is accordance with the
monitored conversion of 1a under the standard reaction
conditions (Figure 1A). Notably, the selectivity toward the
aldehyde 7a over ketone 9a was >99:1. All other tested LAs
proved to be less efficient and led to lower selectivities and/or
conversions. The isomerization of the internal epoxide 3a was
also investigated (Figure 3B); in the presence of Er(OTf)3, a
conversion of 81% for 3a after 1 h at 45 °C was obtained. In
this case, an excellent selectivity of >99:1 toward the ketone 8a
was achieved. All other tested isomerization catalysts which are
frequently used led to lower conversions and poor selectivities
towards 8a.
Next, we investigated the reduction of intermediate 7a and
8a under different conditions (Figure 4). Under the standard
reaction conditions, the conversion of 7a led to the desired
alcohol 2a in 93% yield (Figure 4A). Berke and co-workers
reported the metal-free reduction of ketones and aldehydes
with ammonia borane.44 Notably, if THF was used as the
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presence of Er(OTf)3, only a small amount of molecular
hydrogen (approx. 0.1 equiv in regard to the amount of
employed ammonia borane) was observed.38 The products of
ammonia borane dehydrogenation were analyzed by 11B NMR
spectroscopy, and typical cyclic oligomers were formed.
Furthermore, cross experiments to reduce 1a using molecular
hydrogen instead of ammonia borane gave only low
conversions and 2a in yields <10% (e.g. Figure 1B, entry
4).38 As the direct reduction of the aldehyde intermediate 7a
by ammonia borane and the hydrogenation by molecular
hydrogen can be ruled out (Figures 1B and 2B), we conclude
that the reduction of 7a proceeds via a stepwise hydrogen
transfer process from the ammonia borane to the carbonyl
group. In agreement with these assumptions, 4a-D was
obtained as the final product when 3a was converted in the
presence of ND3BD3 in a deuterium-labeling experiment
(Scheme 3).
the coordination of the ketone and subsequent reduction
leading to the formation of a Co alkoxide. This is in
accordance with the reduction of carbonyl compounds with
other metal PNP catalysts.54 Subsequent protonation of the
alkoxide with ammonia borane and hydride transfer to the
cobalt would lead to the formation of the corresponding
alcohol, regenerate the Co hydride species, and form transient
aminoborane H2BNH2, which further couples to yield
spectroscopically observed oligomeric B−N products.
Based on these findings, we propose the mechanism
depicted in Scheme 4. In the first catalytic cycle, the epoxide,
for example, styrene oxide (1a), is regioselectively isomerized
to intermediate 7a. This isomerization occurs via the activation
of the epoxide 1a by the erbium-salt, followed by the formation
of 1a−2. A subsequent [1,2]-hydride shift leads to
intermediate 7a. The aldeyhyde 7a enters the second catalytic
cycle in which 7a is reduced by Co-IV-1 to the anti-
Markovnikov alcohol 2a and Co-IV-3. The latter is reduced by
ammonia borane to form BN oligomers as the side product
regenerating Co-IV-1.
Scheme 3. Deuterium-Labeling Experiments
In summary, we report a catalytic system based on Er(OTf)3
as a highly efficient isomerization catalyst in combination with
a cobalt PNP complex that enables the transfer hydrogenation
of the carbonyl intermediate. This system allows the
conversion of numerous epoxides to anti-Markovnikov
alcohols at low reaction temperatures (≤55 °C) and short
reaction times (8 h). Notably, comparably low loadings for the
transfer hydrogenation (1.0 mol %) and isomerization catalyst
(3.0 mol %) were required. Ammonia borane was used as a
bench-stable and practical hydrogen source avoiding the use of
molecular hydrogen at high pressures. It was shown that this
catalytic system is more efficient compared to other known
protocols. Moreover, it is broadly applicable and allows the
conversion of a variety of terminal (23 examples) and 1,2-
disubstituted internal epoxides (14 examples) into the desired
anti-Markovnikov alcohols in excellent selectivity and yields of
Furthermore, a mercury test was performed, and a similar
yield of the alcohol was obtained, indicating that the active
species is a homogenous cobalt complex.38 For the hydro-
genation step at the Co complex, we suggest the initial
formation of a Co hydride species which has been proposed by
Luo and Liu for catalyst Co-I in the transfer hydrogenation of
alkynes.36 Indeed, Chirik and co-workers previously reported
the formation of a [(PNP)CoH] complex by treating
(PNP)CoCl2 with a hydride source (NaHBEt3).53 The
formation of the metal hydride species is likely followed by
Scheme 4. Mechanistic Proposal for the Erbium-Catalyzed Regioselective Isomerization−Cobalt-Catayzed Transfer
Hydrogenation Sequence of the Model Substrate Styrene Oxide (1a)
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up to 98%. It was shown that the reaction can even be
performed on larger scale (50 mmol). Notably, the
regiochemistry of the reaction is controlled by electronic
effects, namely, the formation of the most stable carbocation in
the rearrangement step. Thus, the conversion of tri- and tetra-
substituted epoxides was also possible but was in some cases
accompanied by a rearrangement of the carbon framework.
Detailed mechanistic investigations support the proposed two-
step reaction sequence which proceeds via an initial isomer-
ization catalyzed by the LA followed by a transfer hydro-
genation catalyzed by the Co−PNP complex. It was also
revealed that a stepwise transfer of hydrogen from the
ammonia borane to the substrate takes place rather than
dehydrogenation of ammonia borane and subsequent hydro-
genation. Moreover, a significant influence of the LA on the
transfer hydrogenation step was observed.
ABBREVIATIONS
■
NMR, nuclear magnetic resonance; GC, gas chromatography;
LA, Lewis acid; Tf, triflate; THF, tetrahydrofuran
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c03294.
■
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AUTHOR INFORMATION
Corresponding Author
■
Thomas Werner − Leibniz Institute for Catalysis, Rostock D-
18059, Germany; orcid.org/0000-0001-9025-3244;
Email: Thomas.Werner@catalysis.de
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Authors
Xin Liu − Leibniz Institute for Catalysis, Rostock D-18059,
Germany
Lars Longwitz − Leibniz Institute for Catalysis, Rostock D-
18059, Germany
Brian Spiegelberg − Leibniz Institute for Catalysis, Rostock D-
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Torsten Beweries − Leibniz Institute for Catalysis, Rostock D-
18059, Germany; orcid.org/0000-0002-2416-8874
Complete contact information is available at:
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Funding
Chinese Scholarship Council (CSC) to X.L.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dedicated to Paul Kamer, a great scientist and inspiring
person. X.L. is grateful for the financial support of the Chinese
Scholarship Council (CSC). This work was conducted in the
scope of the Leibniz Science Campus Phosphorus Research.
The support of Prof. J. G. de Vries is very much appreciated.
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