Acidic Co-Catalysts in Cationic Gold Catalysis

Article abstract of DOI:10.1002/chem.201603478

A systematic study on the effects of Lewis or Br?nsted acid co-catalysts in gold-catalyzed reactions was undertaken using representative reactions (O-, N-, and C-nucleophilic additions to alkynes). Through these reactions, it was demonstrated that an acidic co-catalyst can increase the catalyst turnover significantly, enabling practical reaction rates at competitive catalyst loadings (<1 mol %). Further investigation is currently underway to improve the understanding of the subtle principles underlying these experimental observations.

Full text of DOI:10.1002/chem.201603478

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Title: Acidic co-Catalysts in Cationic Gold Catalysis
Authors: Gerald Hammond; Bo Xu; Pablo Barrio; Manish Kumar; Zhichao Lu; Junbin
Han
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Acidic co-Catalysts in Cationic Gold Catalysis**
Pablo Barrio,a Manish Kumar,b Zhichao Lu,b Junbin Han,b Bo Xu,c* Gerald B. Hammondb*
Abstract: A systematic study on the effects of Lewis or Brønsted
acid co-catalysts in gold catalyzed reactions was undertaken using
representative reactions (O-, N-, and C-nucleophilic additions to
alkynes). Through these reactions, it was demonstrated that an
acidic co-catalyst can increase the catalyst turnover significantly,
enabling practical reaction rates at competitive catalyst loadings (<1
mol%). Further investigation is currently underway to improve the
understanding of the subtle principles underlying this experimental
observations.
This enhanced acidity could also assist in the protodeauration
stage (Scheme 1b, Stage 2). Other possible helpful roles of the
combined acidic co-catalyst system are: i) converting the
inactive acetylide-gold complex A—formed by abstraction of the
acetylide proton in a terminal alkyne by a cationic gold catalyst
under basic conditions[6]—back to its active state (Scheme 1c);
ii) shielding the active gold catalyst from decay, which is a major
factor in diminishing turnover. We have reported[4e] that
unsaturated substrates such as alkynes, alkenes or allenes
induce the disproportionation of cationic gold (I) catalysts
(Scheme 1d).
In the last two decades gold catalysis has moved to the forefront
of organic synthetic methodologies.[1] However, despite its
synthetic advantages, gold catalysis suffers from important
limitations, including low turnover number (TON) and high gold
catalyst loadings (e.g. 5 mol%), making its use impractical in
large-scale synthesis. The combination of a gold catalyst with
Lewis or Brønsted acidic co-catalysts has, sometimes, given
better efficiency compared to the gold catalyst alone.[2] A typical
example is the Au/Ga co-catalyzed Nakamura reaction (addition
of 1,3-dicarbonyl compounds to terminal alkynes) reported by
Shi and coworkers.[3] During the course of our work to improve
the efficiency of gold catalysis[4] we found that Lewis or Brønsted
acidic co-catalysts are not always helpful in gold-catalyzed
reactions and that different co-catalysts often exhibit different
effects. An acidic co-catalyst does not catalyze the reaction
efficiently by itself but when it is used in conjunction with a gold
catalyst increases the rate of a reaction through synergism. The
detailed mechanism on how acidic co-catalysts work in gold
catalysis is still elusive. The lack of a mechanistic understanding
has hampered the rational use of acidic co-catalysts in gold
catalyzed reactions. Herein, we describe a systematic study on
the effects of Lewis or Brønsted acid co-catalysts, by surveying
representative gold catalyzed reactions.
Since a cationic gold catalyst is a Lewis acid in itself, the
combination of gold with acidic co-catalysts can be considered a
combined acid catalysis. The concept of combined acid catalysis
was first proposed by Yamamoto and coworkers.[5] With this
concept in mind, we proposed that the acidity of a cationic gold
could be enhanced via Brønsted acid-assisted Lewis acid
catalysis or Lewis acid-assisted Lewis acid catalysis (Scheme
1a). This combined acid system should, in principle, generate a
cationic gold species with stronger Lewis acidity. A typical gold
catalytic cycle goes through several stages (Scheme 1b). An
enhanced acidity could promote binding of the cationic gold with
an alkyne/alkene and enable a nucleophilic attack (Stage 1).
Scheme 1. Combined acid catalysis in a typical gold catalytic cycle
(using L-Au-OTf as an example of a cationic gold catalyst).
Among the above proposed effects, the effect of acids on
protodeauration can be easily verified. We investigated the
reaction of preformed vinyl gold complexes with different acids.
We have previously reported that gold complex 1 can be readily
isolated from the gold catalyzed cyclization of allenoates.[7]
Reaction of 1 with acids of various strengths indicated that a
stronger acid produced
a higher rate of protodeauration
(Scheme 2a).[4h] Yu and coworker also reported that the
protodeauration of gold complex 3 followed first order kinetics for
both gold complex and acid (Scheme 2b).[8]
[a]
[b]
Dr. Pablo Barrio, Departamento de Química Orgánica. Universidad
de Valencia. E-46100 Burjassot, Spain
Prof. Gerald B. Hammond, Department of Chemistry, University of
Louisville, Louisville, Kentucky 40292, USA;
E-mail: gb.hammond@louisville.edu
Altogether, these data indicated that the strength and
concentration of acid were directly related to the kinetics of the
protodeauration step. So, in theory, if the protodeauration is the
[c]
Prof. Bo Xu, College of Chemistry, Chemical Engineering and
Biotechnology, Donghua University, 2999 North Renmin Lu,
Shanghai 201620, China
rate-determining step,
a suitable acid co-catalyst should
enhance the overall rate. In order to get an improved picture of
the co-catalyst effect, we surveyed a representative number of
gold catalyzed reactions.
E-mail: bo.xu@dhu.edu.cn.
Supporting information for this article is given via a link at the end of
the document.
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acidic co-catalyst, namely the prevention of catalyst
deactivation.[4e] Still one more different role might be envisaged
for the acidic co-catalyst, namely shortening the incubation time.
This has been observed in some reactions, i.e. the hydration of
internal alyphatic alkynes (Figure 4); however the underlying
mechanism is still not clear. Interestingly, the reaction rate
acceleration wasn't co-catalyst loading dependent.
Ga(OTf)3 0.6%
HOTf 0.6%
100
80
60
40
20
0
HNTf2 0.6%
Scheme 2. Study of protodeauration using acids of different strength.
Addition of a nitrogen nucleophile to an alkyne. We used the
hydroamination of phenylacetylene[9] as a model system to study
the effect of co-catalysts in N-H addition processes (Figure 1).
Several Brønsted or Lewis acids were evaluated (Figure 1a). All
the acid co-catalysts increased the rate of the reaction except
AgOTf; this is consistent with our earlier report that showed that
a silver salt could complex with key gold intermediates, thus
reducing the efficiency of the gold catalyst.[4b] We noted a linear
relationship between the reaction rate and the co-catalyst
loading, which is consistent with our earlier studies (Figure
1a)).[4h] This enhanced reactivity could be attributed to a faster
protodeauration (Scheme 1b) or a reactivation of the acetylide-
Au complex (Scheme 1c). A very strong effect was also
observed in the isomerization of alkynylaziridine to the
corresponding pyrrole derivatives (eq 1).
Addition of an oxygen nucleophile to an alkyne. The
beneficial effect of an acidic co-catalyst in gold catalysis is not
limited to hydroaminations. Hydration of alkynes, and related
reactions, are well studied gold-catalyzed processes.[4a,10] We
used the hydration of 1-octyne 10 as a model reaction and found
that the reaction rate was enhanced in the presence of an acidic
co-catalyst (Figure 2a). This result was experimentally
corroborated when different concentrations of co-catalyst
maintained the same kinetic profile (Figure 2b). This result was
further substantiated with the study of co-catalyst effects on the
hydration of propargyl acetate (eq 2). As it was the case in the
hydroamination of an alkyne, the enhanced reactivity could be
attributed to a faster protodeauration (Scheme 1b) or the
reactivation of the alkyne-Au complex (Scheme 1c).
no co-catalyst
AgOTf 0.6%
4 5
0
1
2
3
time / h
100
80
60
40
20
0
In(OTf)3 0.6%
In(OTf)3 0.3%
In(OTf)3 0.1%
no co-catalyst
0
1
2
3
4
5
time / h
Figure 1. Effect of co-catalyst in hydroamination reaction.
We also investigated the hydration of internal alkynes. A
pronounced effect was observed when using a diaryl internal
acetylene 14 (Figure 3). In the absence of an acidic co-catalyst,
this reaction did not take place at all even after 4 h at 60 ºC
(Figure 3). This lack of reactivity was most likely due to the
deactivation of the gold catalyst, since the formation of black
solid deposits were immediately observed upon addition of the
substrate. However, in the presence of both Lewis and Brønsted
acidic co-catalysts, the reaction proceeded smoothly. No black
solid deposit was observed, suggesting a different role for the
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Ga(OTf)3 1%
Ga(OTf)3 2%
HNTf2 2%
40
30
20
10
0
100
TfOH 2%
HOTf 1%
80
60
40
20
0
In(OTf)3 2%
no co-catalyst
no co-catalyst
20 25
0
50
100
150
200
250
0
5
10
15
time / min
time / h
Figure 3. Effect of co-catalyst on the reaction rate.
100
80
60
40
20
0
Ga(OTf)3 2%
Ga(OTf)3 1%
Ga(OTf)3 0.5%
80
HOTf 1%
60
Ga(OTf)3 1%
no co-catalyst
40
20
0
0
5
10
15
20
25
no co-catalyst
time / h
Figure 2. a) Effect of co-catalyst on the reaction rate; b) effect of co-catalyst
loading on the rate of the reaction.
0
20
40
60
80
100
120
time / min
100
Ga(OTf)3 1.5%
Ga(OTf)3 1%
Ga(OTf)3 0.5%
80
60
40
20
0
0
60
120
180
240
time / min
Figure 4. Effect of co-catalyst on the reaction rate at low loading of gold
catalyst.
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Figure 6. Effect of co-catalyst on the reaction rate using a low oading of gold
catalyst.
Addition of a carbon nucleophile to an alkyne. First, we
investigated the acidic co-catalyst effect in the Nakamura
reaction at room temperature (Figure 5).[3] Contrary to other
reactions, the conversion was very low even when a high
catalyst loading (5%) was employed. Among the many co-
catalysts tested, only very strong Lewis acids like In(OTf)3 and
Ga(OTf)3 were useful (Figure 9a); In(OTf)3 being the most
effective.[11] TfOH had less effect on this reaction (Figure 5a) and,
again, the reaction rate could be directly correlated with the
concentration of co-catalyst (In(OTf)3) (Figure 5b). We also
investigated the Conia-ene reaction,[12]--the intramolecular
version of Nakamura reaction (Figure 6)--and found that co-
catalysts enhanced the rate oft he reaction significantly.
100
80
In(OTf)3 5%
60
40
20
0
Ga(OTf)3 5%
HOTf 5%
no co-catalyst
We found that the co-catalyst effect was negligible or
marginal in other gold catalyzed reactions. Examples included
the cycloisomerization of propargylic amide 20[13] (Figure 7a),
the hydroarylation of 22 (Figure 7b),[14] an oxygen transfer
reaction (Figure 7c),[15] the isomerization of allenyl carbinol ester
0
5
10
15
20
25
30
time / h
60
40
20
0
In(OTf)3 5%
25 (Figure 7d),[16] the cycloisomerization of 1,6-enyne 27
[17]
(Figure 7e)
and the carboalkoxylation of 29 (Figure 7d).[16]
Our preliminary explanation for this lack of co-catalyst effect was
that that the protodeauration step and/or gold catalyst
deactivation were not limiting factors in the catalytic cycle.
Further investigation is required to understand why acidic co-
catalysis may be beneficial for some transformations while for
others is not.
In(OTf)3 2.5%
In(OTf)3 1%
10
0
5
time / h
Figure 5. a) Effect of co-catalyst on the reaction rate at low loading of gold
catalyst. b) Effect of increasing co-catalyst loading maintaining constant the
loading of gold catalyst.
In(OTf)3 0.4%
80
60
Ga(OTf)3 0.4%
40
no co-catalyst
20
0
0
5
10
15
20
25
30
time / min
Figure 7. Reactions in which the effect of a co-catalyst on the reaction rate is
small.
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The use of a co-catalyst can significantly improve the
turnover number of gold catalyzed reactions as we
demonstrated in Scheme 3. Indeed, we achieved a highly
[2]
efficient hydration[4a]
,
hydroamination[18] and Nakamura
reaction[18] under very mild conditions (room temperature) using
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study showcases that an increase of the effective concentration of
the reactive species can be ruled out as an alternative activation
mode for the co-catalyst. The corresponding spectra have been
included in the SI.
In conclusion, an acidic co-catalyst can effectively increase the
turnover of many gold catalyzed reactions, enabling practical
reaction rates at competitive catalyst loadings (<1 mol%).[19]
Even if the mechanism by which such increase in reaction rate
and the factors dictating what type of reactions might benefit
from the use of acidic co-catalysis remain somewhat obscure,
we believe that screening acid co-catalysts should be routinely
considered during reaction optimization in gold catalysis.
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Acknowledgements
[14]
[15]
[16]
[17]
We are grateful to the National Science Foundation for financial
support (CHE-1401700). BX is grateful to the National Science
Foundation of China for financial support (NSFC-21472018).
Keywords: gold catalysis · co-catalyst · catalyst decay · Lewis
acid · transition metal
[18]
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Control experiments in the absence of gold catalyst were carried
out and, in all cases, no-reaction was observed.
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Chemistry - A European Journal
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COMMUNICATION
Pablo Barrio, Manish Kumar,
Zhichao Lu, Junbin Han, Bo Xu,*
Gerald B. Hammond*
A systematic study on the effects
of Lewis or Brønsted acid co-
catalysts in gold catalyzed
reactions was undertaken using
representative reactions (O-, N-,
and C-nucleophilic additions to
alkynes). Through these
Page No. – Page No.
Title
reactions, it was demonstrated
that an acidic co-catalyst can
increase the catalyst turnover
significantly, enabling practical
reaction rates at competitive
catalyst loadings.
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