Asymmetric Guerbet Reaction to Access Chiral Alcohols

Article abstract of DOI:10.1002/anie.202003104

The first example of an asymmetric Guerbet reaction has been developed. Using commercially available, classic Noyori Ru^II-diamine-diphosphine catalysts, well-known in asymmetric hydrogenation, racemic secondary alcohols are shown to couple with primary alcohols in the presence of a base, affording new chiral alcohols with enantiomeric ratios of up to 99:1. Requiring no reducing agents, the protocol provides an easy, alternative route for the synthesis of chiral alcohols. Mechanistic studies reveal that the reaction proceeds via a Ru-catalyzed asymmetric hydrogen autotransfer process in concert with a base-promoted allylic alcohol isomerization.

Full text of DOI:10.1002/anie.202003104

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Accepted Article
Title: Asymmetric Guerbet Reaction to Access Chiral Alcohols
Authors: Kun Wang, Lin Zhang, Weijun Tang, Huaming Sun, Dong
Xue, Ming Lei, Jianliang Xiao, and Chao Wang
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10.1002/anie.202003104
Angewandte Chemie International Edition
RESEARCH ARTICLE
Asymmetric Guerbet Reaction to Access Chiral Alcohols
Kun Wang,[a] Lin Zhang,[b] Weijun Tang,[a] Huaming Sun,[a] Dong Xue,[a] Ming Lei,[b] Jianliang Xiao,[a,c]
and Chao Wang*[a]
Abstract: The first example of asymmetric Guerbet reaction has
been developed. Using commercially available, classic Noyori Ru(II)-
diamine-diphosphine
catalysts,
well-known
in
asymmetric
hydrogenation, racemic secondary alcohols are shown to couple
with primary alcohols in the presence of a base, affording new chiral
alcohols with enantiomeric ratios of up to 99:1. Requiring no
reducing agents, the protocol provides an easy, alternative route for
the synthesis of chiral alcohols. Mechanistic studies reveal that the
reaction proceeds via
a Ru-catalyzed asymmetric hydrogen-
autotransfer process in concert with a base-promoted allylic alcohol
isomerization.
Introduction
Guerbet reaction, i.e. the coupling of two primary alcohols to
give a new alcohol product, was discovered more than 100
years ago by Marcel Guerbet (Figure 1a).[1] Since its discovery,
the reaction has been extensively studied and found broad
applications in the production of plasticizers, lubricants, fuels,
fuel additives, and personal care products.[2] The alcohols so
formed are chiral, but racemic. If the Guerbet reaction could be
made enantioselective, it would provide an appealing new
approach to accessing chiral alcohols that deviates from the
most-widely
practiced
asymmetric
hydrogenation[3]
or
asymmetric transfer hydrogenation[4] of ketones, necessitating
no reducing agents and producing water as the only byproduct.
Optically active chiral alcohols serve as versatile chiral synthons
for the production of numerous pharmaceuticals, agrochemicals
and fine chemicals. However, to the best of our knowledge, an
asymmetric variant of the Guerbet reaction remains unknown.
Mechanistically, the cross coupling of racemic secondary
alcohols with primary alcohols shares the same mechanism as
the typical Guerbet reactions, with all proceeding via
“borrowing hydrogen” or hydrogen autotransfer process.[5]
a
A
large number of catalysts have been reported to catalyze this
transformation to give racemic alcohol products (Figure 1b).[6] In
related studies, Nishibayashi,[7] Adolfsson,[8] Donohoe[9] and their
co-workers showed that enantioenriched alcohol[7,8] or ketone[9]
products could be obtained in the cross coupling of ketones with
Figure 1. Guerbet reaction, cross coupling of ketones with alcohols and cross
coupling of alcohols via hydrogen autotransfer.
alcohols using chiral Ru or Ir catalysts (Figure 1c). However,
asymmetric cross coupling of two alcohols remains elusive. We
hypothesized that if
a chiral catalyst capable of both
dehydrogenation and hydrogenation reactions could be found, it
might be possible to make the borrowing hydrogen or Guerbet
reaction enantioselective. Although dehydrogenation and hence
racemization of the product by the same catalyst are also likely,
the increased steric bulkiness in the product would hinder this
reaction. Herein, we disclose that by employing a Noyori Ru-
diamine-diphosphine catalyst, well-known in asymmetric
hydrogenation, enantiomerically enriched chiral alcohols could
be produced from the cross coupling of racemic secondary
alcohols with primary benzylic alcohols, providing the first
examples of asymmetric Guerbet reaction. The catalysis
disclosed also adds a new transformation to the asymmetric
“borrowing hydrogen” reactions[10] reported by Nishibayashi,[7]
Williams,[11] Oe,[12] Adolfsson,[8] Zhao,[13] Beller,[14] Rodriguez,[15]
[a]
K. Wang, Prof. Dr. W. J. Tang, Prof. Dr. D. Xue, Prof. Dr. J. L. Xiao,
Prof. Dr. C. Wang
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry
of Education, School of Chemistry and Chemical Engineering,
Shaanxi Normal University, Xi’an, 710062, China
E-mail: c.wang@snnu.edu.cn
[b]
[c]
L. Zhang, Prof. Dr. M. Lei
State Key Laboratory of Chemical Resource Engineering, Institute of
Computational Chemistry, College of Chemistry, Beijing University
of Chemical Technology, Beijing, 100029, China
Prof. Dr. J. L. Xiao
Department of Chemistry, University of Liverpool, Liverpool, L69
7ZD, UK
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1. Optimization of the reaction conditions for β-alkylation of 1-
phenylethanol with 4-tolylmethanol.
asymmetric coupling of 1-phenylethanol 1a with 4-tolylmethanol
2a (Table 1). Pleasingly, we found that amongst the catalysts
screened, the Ru(II)-diamine-diphosphine complex 3a, which
was developed by Noyori, Ohkuma and co-workers for
asymmetric hydrogenation of ketones,[19] could catalyze the
coupling of 1a with 2a, affording 4a with 48% yield and 68:32 er
o
in the presence of 0.25 equivalent of NaOH at 80 C for 12 h
(Table 1, entry 1). The observation is somewhat surprising, as
such Ru complexes have rarely been used in asymmetric
hydrogen transfer reactions.[20] Decreasing the reaction
temperature led to much higher enantioselectivities, albeit with
lower yields (Table 1, entries 2-3).
A
slightly better
enantioselectivity and similar yield was obtained by replacing
NaOH with tBuOK as base (Table 1, entry 4). In comparison, the
other
hydrogenation catalysts afforded inferior asymmetric induction,
except catalyst 3c which showed similar activity and
commercially
available
hydrogenation/transfer
a
enantioselectivity to 3a (Table 1, entries 5-9, see more examples
in Table S3 in the SI). Notably, the more electron-rich 3f
displayed a much higher activity, with the product being almost
racemic though (Table 1, entry 9). Further optimization of
reaction conditions, including solvent, the amount of base,
substrate ratio, and time (see SI for details), led to the alcohol 4a
being isolated in a good yield of 64% with a high enantiomeric
ratio of 93:7, using 1 mol% of 3a, 1 equivalent of tBuOK, and 3
equivalents of 1a (relative to 2a) at 60 oC for 12 h (Table 1, entry
11). Although the yield of 4a could be further increased by
prolonging the reaction time, the enantioselectivity was found to
decrease (vide infra). The reaction was shown to be feasible at a
higher S/C of 200, affording 35% yield and 96:4 er in 12 h (Table
1, entry 12). The configuration of the major enantiomer 4a was
determined to be S by single-crystal X-ray diffraction, as shown
in Table 1.
2. Substrate scope, gram-scale reaction and synthetic
application. We went on to explore the substrate scope of the
reaction using the conditions shown in entry 11 of Table 1 with
3a or 3c as catalysts (Figure 2, see section 4 in the SI for
detailed conditions). The reaction of various racemic secondary
alcohols with primary benzylic alcohols was first examined
(Figure 2, 4a-4u). As can be seen, the alcohols were obtained in
good to excellent enantioselectivities. However, this is achieved
at the expense of yield to some degree. In particular, in order to
obtain acceptable enantioselectivities for para and meta-
substituted secondary alcohols (4b-4j), the product yields need
to be controlled to be moderate, as the er would erode at higher
conversions (vide infra). Interestingly, we noted that substrates
with an ortho-methyl group on the phenyl ring of 1-
phenylethanols generally afforded better results in terms of both
yields and enantioselectivities, e.g. 4k-4o vs 4a-4e. Notably, 4l
was obtained in 75% NMR yield and 99:1 er. This ortho-methyl
effect presumable stems from the increased steric hindrance in
the product that inhibits dehydrogenation-triggered racemization.
Aliphatic secondary alcohols could also react, as exemplified
with 4p, albeit with a low enantioselectivity, which could be
improved via recrystallization. A furan heterocycle could be
tolerated (4u). Realizing the ortho-methyl effect, the coupling of
(2,4-dimethylphenyl)ethan-1-ol (1m) with various primary
alcohols was next investigated (Figure 2, 5a-5ad). High
enantioselectivities were observed for these couplings with
[a] Reaction conditions: 1a (1 mmol), 2a (1 mmol), catalyst (1 mol%), toluene
(2 mL) under Ar, 12 h, isolated yield. [b] The enantiomeric ratio (er) was
determined by HPLC analysis of pure isolated product, and the absolute
configuration was determined by X-ray crystallography. [c] R-4a was the major
product. [d] 1a : 2a = 3 : 1. [e] 1a : 2a = 3 : 1, with 0.5 mol% catalyst.
Zhou,[16] Popowycz,[17] Donohoe[9] and Dydio.[18] It proceeds via
an interesting cooperative Ru-catalyzed hydrogen autotransfer
and base-catalyzed isomerization process (Figure 1d).
Results and Discussion
1. Reaction development. We commenced our studies by
screening of a variety of known asymmetric hydrogenation
catalysts, in the hope to find a catalyst that would enable the
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Figure 2. Substrate scope for asymmetric β-alkylation of secondary alcohols with primary alcohols. Reaction conditions: secondary alcohol (3 mmol), primary
alcohol (1 mmol), tBuOK (1 mmol), catalyst (1 mol%), toluene (2 mL), under Ar, Isolated yield. The products could not be totally separated from unreacted
substrates via silica chromatography for examples with only 1H NMR yields. The enantiomeric ratio (er) was determined by HPLC analysis of pure isolated product
for all the examples. See SI for detailed reaction conditions. [a] 3c was used as catalyst. [b] 1H NMR yield with 1,3,5-trimethoxybenzene as an internal standard.
[c] 2mol% of 3a was used.
synthetically sensible yields in general (> 90:10 er for all, and
notably 99:1 er for 5u). The electronic properties of substituents
on the phenyl rings of the primary benzylic alcohols appear to
affect their activities slightly, with electron-donating groups
performing better than electron-withdrawing ones (5b-5d, 5g vs
5i-5l). Again, para, meta and ortho-substituents on the phenyl
rings of these alcohols are all tolerated. Worth noting are
substrates with N, O and S-containing heterocycles, which are
viable for the reaction (5f, 5ab-5ad). However, aliphatic primary
alcohols failed to give the desired product, probably due to the
complex reactivity of the aliphatic aldehyde intermediates.
The utility of the protocol is further demonstrated by a gram-
scale reaction and synthetic application of one of the alcohol
products (Figure 3). Thus, coupling of 1-(2,4-dimethylphenyl)
ethan-1-ol (1m) with (4-morpholinophenyl)methanol (2g)
afforded 1.22 g of 5f with 95:5 er (Figure 3a, section 5 in the SI),
and the alcohol 5s underwent cyclization via Pd-catalyzed
intramolecular C-O bond coupling to form a chiral chroman
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RESEARCH ARTICLE
Figure 3. Gram-scale reaction and synthetic applications.
compound 6 with only slight erosion of the enantiomeric ratio
(Figure 3b, section 6 in the SI). This latter reaction provides a
convenient route for accessing chiral chromans, which exist as
the core skeleton of many natural products with biological
activities.[21]
3. Mechanistic studies. To gain mechanistic insight into this
new transformation, a series of probing experiments were then
carried out. Previous studies on achiral cross coupling of
alcohols with transition metal catalysts[6] suggest that the
asymmetric Guerbet reaction under question might proceed via
dehydrogenation of both alcohols to a ketone and an aldehyde,
followed by aldol condensation and reduction (Figure 1d).
Analysis by 1H NMR of the crude reaction mixture resulting from
the coupling 1a with 2a in 30 minutes with 3a as catalyst
revealed indeed the formation of acetophenone (5% yield) and
4-methylbenzaldehyde (ca 1% yield) (Eq. 1, also see section 7.1
in the SI for details). It is conceivable that acetophenone would
condense with 4-methylbenzaldehyde to afford an α,β-
unsaturated ketone 7 under the basic conditions employed, with
or without 3a (Eq. 2, also see section 7.2 in the SI for details).[22]
Figure 4. Time-dependent distribution of substrate, intermediates and product
for 3a catalyzed reduction of 7 with 1a as hydrogen source. Yields and the
quantity of unreacted substrate were determined by 1H NMR with 1,3,5-
trimethoxybenzene as an internal standard.
the SI for details). These observations suggest that 7 could be
first reduced to 8. The allylic alcohol could then be transformed
into the ketone product 9, reduction of which would afford 4a
under the reaction conditions.
If this is the case, another question arises, that is, how the
allylic alcohol 8 could be transformed into the ketone 9. Ohkuma
and co-workers have showed that the 3a type catalyst is unable
to isomerize allylic alcohols,[23] which is also confirmed by our
experiments (see section 7.4.1 in the SI for details). However, it
has been reported that allylic alcohols can be isomerized into
ketones under the catalysis of a base.[24] Indeed, we found that 8
could be isomerized to 9 requiring only a base (section 7.4.1 in
the SI). The cation of the bases appears to be critical for the
isomerization, with tBuOK being the best base (section 7.4.2 in
the SI). When the C1-deuterated allylic alcohol 10 was used, the
majority of the deuterium atoms were transferred from C1 to C3
position of 10, affording 11 (Eq. 3). Moreover, the isomerization
An interesting question then is how 7 would be reduced to
the product 4a. The Noyori Ru-diamine-diphosphine catalysts
are well-known to be selective for the reduction of C=O, instead
of C=C, double bonds in substrates such as α,β-unsaturated
19c]
ketones.[19b,
Monitoring the reduction of 7 with 1a as
reductant and 3a as catalyst showed that only the carbonyl
reduction product 8, an allylic alcohol, was formed in the initial
stage of the reaction in the presence of Cs2CO3 (Figure 4).[22]
This is in line with what would be expected of the Noyori catalyst.
The quantity of 8 decreased after 0.5 h followed by the
appearance of a ketone intermediate 9 and the final product 4a
(Figure 4). The intermediate 8 was then synthesized and
examined. In the presence of 1a (1 equiv.), tBuOK (1 equiv.),
and 3a (1 mol%) in toluene, the allylic alcohol 8 was primarily
converted to 9 (14% yield) and 4a (46% yield) (see section 7.3 in
proceeded equally well in the presence of 1 equivalent of a
radical scavenger, TEMPO (2,2,6,6-tetramethylpiperidinyloxy) or
1,1-diphenylethylene. These results suggest that the
isomerization does not involve a radical mechanism[24a] and may
proceed via an intramolecular 1,3-hydrogen transfer process
proposed by Martín-Matute and co-workers.[24b] Comparing the
isomerization rate of 8 with that of the C1-deuterium labelled 10
revealed an approximate kinetic isotope effect of kH/kD ~ 5
(section 7.4.3 in the SI), suggesting a rate-determining C1-H
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10.1002/anie.202003104
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RESEARCH ARTICLE
secondary alcohol substrate and the product 4a could undergo
racemization under the catalytic conditions (Eqs. 4 and 5).
However, the racemization rate is slower for the product 4a than
for the starting secondary alcohol (Eqs. 4 and 5), which might be
due to the increased steric hindrance in 4a. More significantly,
no racemization was observed for the sterically bulkier product
4k under the same conditions (eq. 6), further corroborating the
argument for steric effect. These observations suggest that both
the substrate and product undergo racemization. However, the
racemization process is sensitive to steric hindrance, with the
bulkier product racemizing slower than the substrate. This
inference may not be surprising, considering the steric hindrance
imposed by the two bulky ligands at the equatorial plane of 3a.
Additional control experiments showed that the racemization
is not catalyzed by 3a (Eq. 7) or promoted by the base alone (Eq.
8). Instead, racemization was observed in the presence of a
ketone and base without 3a (eq. 9), suggesting that the
racemization may proceed via a base and carbonyl intermediate
Figure 5. Free energy profile of the isomerization of a model allylic alcohol to
the enolate intermediate assisted by tBuOK.
cleavage for the isomerization reaction.
The isomerization was further studied with DFT calculations
(section 7.4.4 in the SI). The base mediated 1,3-hydrogen shift
mechanism gives
a
reasonable energy profile for the
isomerization of a model allylic alcohol, with a rate-determining
C1-H cleavage step (TS12-13) involving the participation of K+,
which fits well with the experimental observations and is in line
with the results of Martín-Matute and co-workers[24b] (Figure 5).
Thus, we may conclude that the allylic alcohol 8 is transformed
into the ketone 9 via a base-catalyzed isomerization process.
The reduction of 9 to 4a by 3a should be facile. Indeed, isolated
9 was readily reduced to 4a (90% yield, 94:6 er) with 1a as
hydrogen source (section 7.5 in the SI).
A remaining, intriguing question is why the alcohol product
does not appear to be racemized via dehydrogenation, given the
similarity of the product to the substrate. Monitoring the reaction
of 1a with 2a catalyzed by 3a showed that whilst the yield of 4a
increased with time, the enantioselectivity decreased
considerably from >90% ee to <40% ee over a period of 36 h
(Figure S3 in section 7.6 of the SI), showing that the product 4a
could be racemized under the reaction conditions. Control
experiments further showed indeed that both the starting
through a MPV-type mechanism.[25] As this MPV-type hydrogen
transfer is sensitive to steric hindrance,[25] the racemization of
sterically bulky products would be slow, which fits well with the
experimental results.
The above mechanistic studies support the mechanistic
picture shown in Figure 1d. The two alcohol starting materials
are both first dehydrogenated to give Ru hydride intermediates
and two carbonyl compounds, which condense to afford to an
α,β-unsaturated ketone intermediate in the presence of a base.
The unsaturated ketone intermediate is then reduced by a Ru
hydride to produce an allylic alcohol intermediate, which
undergoes a base-catalyzed isomerization to form a ketone.
Finally, the ketone is reduced by a Ru hydride to afford the chiral
alcohol product. As the chiral center is generated in this step,
the enantioselectivity of the overall reaction should be
determined by the chiral Ru catalyst, in a manner resembling the
related Noyori asymmetric hydrogenation. Whist both the
secondary alcohol substrate and the product could be racemized
via a MPV process, the racemization rate is significantly lower
for the product, due to enhanced steric effects.
Conclusion
In summary, we have developed a chiral version for the century-
old Guerbet reaction, which allows for the asymmetric coupling
of second alcohols with primary alcohols to afford new, chiral
alcohols. Catalyzed by commercially available Ru asymmetric
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10.1002/anie.202003104
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RESEARCH ARTICLE
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hydrogenation catalysts but requiring neither H2 nor any other
reducing agents, this asymmetric Guerbet reaction is highly
enantioselective in general and can be performed at a gram-
scale, providing a convenient new route for the synthesis of
chiral alcohols. Mechanistic studies suggest that the reaction
proceeds via a metal-base cooperative process, with the former
enabling the hydrogen autotransfer reaction while the latter
promoting the isomerization of intermediary allylic alcohols.
[4]
Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21773145), Projects for the Academic
Leaders and Academic Backbones, Shaanxi Normal University
(16QNGG008), and the 111 project (B14041).
[5]
Keywords: chiral alcohol • alkylation • hydrogen autotransfer •
ruthenium • asymmetric catalysis
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Entry for the Table of Contents
RESEARCH ARTICLE
K. Wang, L. Zhang, W. J. Tang, H. M.
Sun, D. Xue, M. Lei, J. L. Xiao, C.
Wang*
Page No. – Page No.
Asymmetric Guerbet Reaction to
Access Chiral Alcohols
Commercially available, classic Noyori Ru(II)-diamine-diphosphine catalysts
catalyze the cross coupling of racemic secondary alcohols with primary alcohols in
the presence of a base, affording new chiral alcohols with enantiomeric ratios of up
to 99:1.
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