Room-Temperature Guerbet Reaction with Unprecedented Catalytic Efficiency and Enantioselectivity

Article abstract of DOI:10.1002/anie.202004758

We report herein an unprecedented highly efficient Guerbet-type reaction at room temperature (catalytic TON up to >6000). This β-alkylation of secondary methyl carbinols with primary alcohols has significant advantage of delivering higher-order secondary alcohols in an economical, redox-neutral fashion. In addition, the first enantioselective Guerbet reaction has also been achieved using a commercially available chiral ruthenium complex to deliver secondary alcohols with moderate yield and up to 92 % ee. In both reactions, the use of a traceless ketone promoter proved to be beneficial for the catalytic efficiency.

Full text of DOI:10.1002/anie.202004758

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Accepted Article
Title: Room-Temperature Guerbet Reaction with Unprecedented
Catalytic Efficiency and Enantioselectivity
Authors: Yu Zhao, Teng Wei Ng, Gang Liao, Kai Kiat Lau, and Hui-Jie
Pan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202004758
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10.1002/anie.202004758
Angewandte Chemie International Edition
COMMUNICATION
Room-Temperature Guerbet Reaction with Unprecedented
Catalytic Efficiency and Enantioselectivity
Teng Wei Ng,[a],+ Gang Liao,[a],+ Kai Kiat Lau,[a] Hui-Jie Pan,[a] and Yu Zhao*[a,b]
Abstract: We report herein an unprecedented highly efficient
Guerbet-type reaction at room temperature (catalytic TON up to
>6000). This β-alkylation of secondary methyl carbinols with primary
alcohols has significant advantage of delivering higher-order
secondary alcohols in an economical, redox-neutral fashion. In
addition, the first enantioselective Guerbet reaction has also been
achieved using a commercially available chiral ruthenium complex to
deliver secondary alcohols with moderate yield and up to 92% ee. In
both reactions, the use of a traceless ketone promoter proved to be
beneficial for the catalytic efficiency.
after decades of efforts.[5] Related to classic asymmetric transfer
hydrogenation of ketones using isopropanol,[6] achieving kinetic
enantioselectivity as well as minimizing product racemization in
such a highly dynamic, reversible process presents a formidable
challenge to overcome.
Alcohols are one of the most fundamental functionalities in
organic compounds. Given its importance as well as the current
strong push for sustainable chemistry, the development of
practical and economical synthesis of alcohols remains a focal
point in synthetic chemistry. Although a plethora of methods have
been developed to synthesize alcohols including enantioenriched
chiral alcohols, most of them rely on the conversion of other
functionalities and especially carbonyls.[1] In these processes, the
necessity to use reactive reductants or organometallic reagents
inevitably led to the generation of stoichiometric amount of salt-
based waste. More economical and environmentally friendly
syntheses of alcohols are still highly desired.
The strategy of borrowing hydrogen has gained much
prominence for enabling redox-neutral synthesis of important
building blocks with high atom-economy.[2] With this regard,
simple feedstock alcohols can be converted to amines or higher-
order alcohols through a one-pot dehydrogenation-condensation-
hydrogenation procedure, with no use of external reagents nor
generation of waste. Historically, the renowned Guerbet reaction
that entails homo-coupling of primary alcohols to forge branched
primary alcohols has found a wide spectra of applications in fine
chemical and biofuel synthesis (Scheme 1a).[3] To extend the
utility of such method, the hetero-coupling of two different alcohols,
and especially β-alkylation of readily available secondary methyl
carbinols with a primary alcohol has been extensively explored in
recent years.[4] Despite the success with various transition-metal
catalyzed systems, all the reported procedures required high
temperature (mostly >100 ˚C) for high efficiency. Very often, the
primary alcohol needs to be used in large excess to overcome the
challenging chemoselectivity in cross aldol condensation.
Addressing such issues is needed to realize the full potential of
this transformation. More significantly, an enantioselective variant
of this attractive higher-order alcohol synthesis remains elusive
Scheme 1. Strategies for the synthesis of higher-order alcohols
In the past few years, our group has been devoted to
enantioselective borrowing hydrogen method development, and
reported the first examples of stereoconvergent amination of
alcohols.[7-9] With an eye on the problem of higher-order alcohol
synthesis, we sought to improve the practicality of the reaction
with a focus on achieving high catalytic efficiency as well as
enantioselectivity under mild reaction conditions. We present
herein an efficient catalytic system that can achieve high catalytic
turnover (TON up to >6000) for β-alkylation of methyl carbinols at
room temperature (Scheme 1b). Efforts for the first
enantioselective Guerbet-type reaction are also disclosed.
We started our investigation by attempting to couple 1-
phenylethanol 1a with benzyl alcohol 2a in 1:1 ratio at ambient
conditions (Table 1). Reactions were performed with 0.5 equiv.
KOtBu in a solution of t-amyl alcohol. Different catalysts that have
been proven to be highly reactive in hydrogen transfer or
borrowing hydrogen reactions were screened. Surprisingly, most
of the catalysts tested failed to give the desired product with
satisfactory results. Reactions catalyzed by ruthenium complexes
were generally inefficient (entries 1–3). We then turned our
attention to iridium catalysts (entries 4–7). To our delight, catalyst
[Ir]-4[7d,10] showed a promising result with 15% yield (entry 7).
Testing the loading of base disclosed that 1.0 equivalent of KOtBu
was optimal (entry 8 vs. entries 7 & 9). However, the yield
remained moderate at this juncture, which left much room for
improvement.
[a]
T. W. Ng, G. Liao, K. K. Lau, H.-J. Pan, and Prof. Dr. Yu Zhao
Department of Chemistry, National University of Singapore, 3
Science Drive 3, Republic of Singapore, 117543
E-mail: zhaoyu@nus.edu.sg
Homepage: http://zhaoyugroup.sg
[b]
[+]
Joint School of National University of Singapore and Tianjin
University, International Campus of Tianjin University, Binhai New
City, Fuzhou 350207, China
These authors contributed equally to this work.
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10.1002/anie.202004758
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COMMUNICATION
Table 1. Optimization of reaction conditions[a]
methyl carbinols, we decided to examine the use of non-methyl
ketones and in particular the smallest 3-pentanone IV. To our
delight, in the presence of 5 mol% IV, 3a was obtained in excellent
yield without any undesired side reactions (entry 15). Importantly,
IV could be easily removed together with the solvent. It thus
represents an ideal, convenient choice of additive.
With the optimal conditions in hand, we moved on to explore
the substrate scope of this catalytic reaction (Scheme 2). Various
secondary alcohols were examined first. Aryl groups with electro-
withdrawing and -donating substituents at the para-position were
all well-tolerated to produce 3b-3j with good to excellent yields. It
is worthy mentioning that halogen and vinyl groups were all
compatible with this reaction, which offered opportunities for
downstream structural modification. Meta- and ortho-substituted
aryl secondary alcohols also participated in the reaction under the
standard conditions with the products obtained in moderate to
high yields (3k-3p). Secondary alcohols bearing naphthyl
substitutes smoothly reacted to yield products 3q-3r in excellent
yields. More significantly, different heteroaryl-containing
secondary alcohols, such as those with pyridine, furan,
benzofuran and benzthiophene were successfully converted to
the corresponding products in good to excellent yields (3s-3v). As
a significant extension of the scope, aliphatic secondary alcohols
were also adapted to the catalytic system with a longer reaction
time, affording the β-alkylated secondary alcohols with moderate
to good yields (3w-3z).
Entry
Catalyst
Additive
Base (equiv.)
Yield(%)[b]
--
--
1
[Ru]-1
[Ru]-2
[Ru]-3
[Ir]-1
[Ir]-2
[Ir]-3
[Ir]-4
[Ir]-4
[Ir]-4
[Ir]-4
[Ir]-4
\
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
2.0
1.0
\
--
--
2
3
--
8
4
--
--
--
6
5
--
6
--
--
7
15
39
18
95
<2
<2
95
85
95
--
8
--
9
5 mol% I
5 mol% I
5 mol% I
5 mol% II
5 mol% III
5 mol% IV
10
11
12
13
14
15
1.0
1.0
1.0
1.0
[Ir]-4
[Ir]-4
[Ir]-4
Next, variations on the primary alcohol counterpart were
examined. Substituted benzyl alcohols with either electro-
donating or electro-withdrawing groups all gave excellent yields
(3aa-3ag). Napthyl and furyl benzyl alcohols likewise were
converted in high yields (3ah, 3ai). Simple linear alcohols was
also subjected to the standard reaction conditions and was found
to give similarly high yields (3aj, 3ak). Finally, a linear primary
alcohol bearing a terminal alkene was also tolerated without
observation of reduction of the alkene moiety (3al).
To further showcase the synthetic utility of this method, a range
of gram-scale reactions were carried out. First, a 10 mmol scale
reaction of 1a with 1b was performed, delivering the product 3a in
96% yield (2.03 g, eq. 1). In addition, in an effort to reduce the
catalyst loading, we were delighted to find that even at 0.01 mol%
loading, [Ir]-4 could promote the reaction with high efficiency
(~6100 TON) in 72 h.
[a] Reaction conditions: 1a (0.4 mmol), benzyl alcohol 2a (0.4 mmol), catalyst
(0.004 mmol), additive, KOtBu (0.4 mmol) in t-amylol (0.2 mL) at 23 oC under
N2 for 24 h. [b] Isolated yield.
We sought to develop an alternative strategy to further
improve the efficiency of the reaction. The use of either the ketone
or aldehyde corresponding to the alcohol substrates as a catalytic
promoter for alcohol coupling has been disclosed.[11] Inspired by
this strategy, we examined the effect of carbonyl promotor by
adding 5 mol% benzaldehyde I to the reaction (entry 10). Under
this set of conditions, the starting materials 1a and 2a were fully
converted to 3a with a trace mount of the corresponding ketone
as a byproduct. To rule out the possibility that our reaction is
solely catalyzed by the carbonyl promoter, control reactions using
I without either the base (entry 11) or [Ir]-4 (entry 12) were
performed. Neither of them gave any desired product, suggesting
that aldehyde I could not catalyzed this reaction alone. Instead, it
was likely promoting the initiation of this Ir-catalyzed process as
the only hydrogen acceptor at the beginning. It is noteworthy that
ketone II could also serve as the hydrogen shuttle to yield 3a with
a similarly high yield (entry 13).
Notably, the use of benzaldehyde or acetophenone will not be
a general solution for a wide range of substrates as they lead to
side product formation. A readily available and easily removable
(traceless) promotor that does not interfere with the borrowing
hydrogen reaction would be much more desirable. In this context,
the use of III led to 3a in slightly lower yield due to the generation
of byproducts (entry 14). Considering that essentially all the
reported β-alkylation of secondary alcohols only worked for
The mechanistically related but simpler alkylation of ketones
using primary alcohol has also attracted much interest in recent
years as an economical method for ketone functionalization.[12]
Without the need for any optimization, our catalytic method could
convert II and 1b to the desired product 4 in high efficiency at mild
conditions (1.8 g, eq. 2). The additive IV was not necessary in this
case as ketone substrate was involved.
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10.1002/anie.202004758
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COMMUNICATION
[a] Unless otherwise noted, the reactions were carried out with 1a (1.0 mmol), benzyl alcohol 2a (1.0 mmol), [Ir]-4 (0.01 mmol), IV (0.05 mmol) and KOtBu (1.0
mmol) in t-amyl alcohol (1.0 mL) at 23 oC under N2 for 24 h. All are isolated yield. [b] 72 h reaction.
Scheme 2. Scope of β-alkylation of secondary alcohols with primary alcohols[a]
A plausible reaction pathway was proposed for this catalytic
system. As depicted in Scheme 3, the active iridium-amide
catalyst generated in situ by the base KOtBu promotes
dehydrogenation of two alcohol substrates to their respective
carbonyl intermediates. We believe that ketone IV plays a
significant role for the reaction initiation. As the only hydrogen
acceptor at the beginning of the reaction with two alcohols 1 and
2 as well as a low concentration of the catalyst, the presence of
IV allows an more efficient build-up of a reservoir of the aldehyde
and ketone intermediates, which undergoes aldol condensation
followed by reduction to deliver the desired product. Conveniently,
IV does not involve in the aldol step so no side product is formed.
In addition, the aldol condensation step likely involves the
Scheme 3. Proposed reaction pathway
equilibrium of a complex mixture, while in the productive pathway
As shown in Scheme 4a, the extensive screening of chiral Ir-
enone 5 undergoes double hydrogenation by the [Ir-H] species to
and Ru-based chiral complexes met with limited success. The
complete the redox cycle.
most promising commercially available [Ru]-8 was chosen for
Despite the attractiveness of this redox-neutral synthesis of
further optimization. The increase in the loading of both ketone IV
higher-order secondary alcohols from simple building blocks, it is
and primary alcohol turned out to be beneficial, which improved
extremely challenging to achieve an enantioselective variant of
the formation of 3a in 29% yield with 92% ee (entry 3 vs. entries
this transformation. The harsh conditions needed for the catalytic
1 & 2). A control reaction without IV led to much lower efficiency
efficiency in previous studies presumably impeded the realization
and ee (entry 4). Finally, 3a was obtained in 42% yield with 90%
of high asymmetric induction during the enantio-determining
ee. Notably, the remaining 1a was recovered with marginal ee
ketone reduction step. In addition, product racemization would be
(49%, 34% ee), suggesting a concomitant resolution of the
a serious hurdle to overcome for such a complex reversible
secondary alcohol substrate. However, all further optimization
system. With the achievement of this reaction under mild
failed at this point.
conditions, we turned our attention to the identification of a
suitable chiral catalytic system to achieve this long-sought-after
goal.
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10.1002/anie.202004758
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As summarized in Scheme 5, variations on both the secondary
alcohol and primary alcohols substrates were well-tolerated. The
resulting alcohol products 3 were obtained in uniformly 84–92%
ee, albeit with low to moderate isolate yield. The identification of
a more reactive catalytic system to achieve high conversion and
kinetic selectivity is under continuous investigation.
In conclusion, we have developed a highly efficient catalytic
redox-neutral β-alkylation of secondary alcohols with primary
alcohols at room temperature. A broad range of higher-order
secondary alcohols are accessible with synthetic useful yields.
Scaling up the reaction with low loading of the catalyst further
highlighted the potential of this reaction for synthetic application.
Importantly, an unprecedent enantioselective variant of this
transformation has been achieved, where kinetic resolution of the
starting secondary alcohol and enantioselective synthesis of the
product alcohol proceed simultaneously.[13] The development of
more efficient and selective catalytic system and extension to
other related transformations are underway in our laboratory.
b) yield & ee vs. reaction time
Acknowledgements
We are grateful for the financial support from the Ministry of
Education of Singapore (R-143-000-A94-112 and R-144-000-
420-112) and National University of Singapore (R-143-000-A57-
114).
Scheme 4. Screening of reaction conditions for enantioselective variant
Keywords: Guerbet reaction • borrowing hydrogen • higher-
order alcohol • alkylation • enantioselectivity
To better understand this catalytic system, the yield and ee of
both 3a and 1a vs. time was followed (Scheme 4b). The
conversion to 3a gradually increased but stopped at ~40% yield,
while a slow racemization of 3a over time was also clearly
observed (from >98% to 90% ee). For this dynamic reversible
transformation, the catalyst is clearly doing redox chemistry on
both the substrate and product, and the high kinetic selectivity
slowly diminished when the conversion went on. While this does
not provide a high-yield stereoconvergent synthesis of higher-
order secondary alcohols, we decided to move on to probe the
generality of this catalytic enantioselective Guerbet-type reaction
nonetheless.
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Scheme 5. Scope of enantioselective Guerbet-type reaction
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Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Teng Wei Ng, Gang Liao, Kai Kiat Lau,
Hui-Jie Pan and Yu Zhao*
Page No. – Page No.
Room-Temperature Guerbet Reaction
with Unprecedented Catalytic
Efficiency and Enantioselectivity
We report herein an unprecedented highly efficient Guerbet-type reaction at room
temperature (catalytic TON up to >6000). This β-alkylation of secondary methyl
carbinols with primary alcohols has significant advantage of delivering higher-order
secondary alcohols in an economical, redox-neutral fashion. In addition, the first
enantioselective Guerbet reaction has also been achieved using a commercially
available chiral ruthenium complex to deliver secondary alcohols with moderate yield
and up to 92% ee.
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