An Industrial Perspective on Counter Anions in Gold Catalysis: Underestimated with Respect to “Ligand Effects”

Article abstract of DOI:10.1002/adsc.201800233

The conversion of a variety of well-known test reactions, representing the key reactivity patterns of gold catalysis, were analyzed by GC and ¹H NMR. The study is focused on establishing of a strategical approach for the consideration of ligand

Full text of DOI:10.1002/adsc.201800233

Title: An Industrial Perspective on Counter Anions in Gold Catalysis:
Underestimated with Respect to “Ligand Effects”
Authors: Jasmin Schießl, Jürgen Schulmeister, Angelino Doppiu,
Eileen Wörner, Matthias Rudolph, Ralf Karch, and A. Stephen
K. Hashmi
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800233
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
An Industrial Perspective on Counter Anions in Gold Catalysis: Underestimated
with Respect to “Ligand Effects”
Jasmin Schießl,a,b Jürgen Schulmeister,a,b Angelino Doppiu,c Eileen Wörner,c Matthias
Rudolph,a Ralf Karch,c A. Stephen K. Hashmia,*
a Innovam, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.
b Organisch-Chemisches Institut, Heidelberg University, Im Neuenheimer Feld 270,
69120 Heidelberg, Germany.
c Umicore AG & Co. KG, Rodenbacher Chaussee 4, D-63457 Hanau-Wolfgang,
Germany.
Abstract
The conversion of a variety of well-known test reactions, representing the key reactivity
patterns of gold catalysis, were analyzed by GC and 1H NMR. The study is focused on
establishing of a strategical approach for the consideration of ligand influence and
counter anion influence during the catalyst optimization including an industrial
perspective. The study shows a dominance of the counter anion, a dominance which
up to now has been neglected in most of the routine screenings. In addition, a drastic
substrate-dependency became obvious, even a marginal variation of the substrate
already could strongly effect the catalytic activity and change the optimal counter anion
or ligand. Based on the collected data a strategic concept for an efficient screening for
a specific substrate is introduced, this concept can serve as an important guideline for
catalyst optimization in homogeneous gold catalysis.
Keywords
Alkynes, allenes; catalyst optimization; counter anion; gold; ligand,
Introduction
Homogeneous gold catalysis evolved into a topic of considerable interest.[1] The
centerpiece in each gold-catalyzed reaction is the gold catalyst. Cationic gold species
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
are considered to be the most effective catalysts in the electrophilic activation of
alkynes for the addition of a diversity of nucleophiles. However, in the literature the
choice of the gold catalyst often seems to be random and so far the strategic approach
to the optimization with respect to the ligand and counter anion of the catalyst is
inadequate, if involved at all.[2] This becomes obvious by an analysis of publications
concerning the most recent experimental studies in gold catalysis published in 2017
(Figure 1: 116 publications at 16.11.2017, Scifinder, keyword: gold catalyzed; only
experimental studies are included). Mainly the ligand system of the gold(I) catalyst was
examined, 31 % of all incorporated publications only deal with ligand variations. 32 %
are based on an initial variation of the ligand, followed by a variation of the counter
anion for the most successful ligand. Thus, overall 63 % are first and foremost focusing
on ligand variations during the catalyst optimization. In 4 % only the counter anion was
varied, in 10 % after the screening of counter anions a ligand variation followed.
Although counter anion effects are well described in literature,[3] the choice of counter
anion is still empirical and its role in screenings is mostly neglected.17 % of the reports
only vary other parameters like substrate concentration, solvent or temperature. In a
few reports (6 %) the catalyst screening is performed without any recognizable pattern.
Overall, the average number of screened ligands is as low as 4.2 per publication, the
average number of applied counter anions is only 2.1. Interestingly, in almost one half
of the reports (31 % + 17 % = 48 %) the counter anion was not varied at all.
4%
10%
6%
32%
17%
only ligand
at first ligand
only counterion
at first counterion
arbitrary
31%
only solvent, temperature, concentration
Figure 1. Overview of the applied catalyst optimization procedures in the year 2017.
This analysis shows that the effect of the ligand[4] is mostly expected to be more
pronounced than counter anion influences in gold(I) catalysis.[5] Only in a few
publications the latter is addressed at all, for example by Zuccaccia and co-workers
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
who examined the counter anion-impact in the gold(I)-catalyzed alkoxylation of alkynes
by DFT calculations.[6] Thereby, they demonstrated an influence of the coordinating
ability, basicity and geometry of the counter anion on all steps of the reaction
mechanism. Furthermore, Hammond and co-workers introduced a method to predict
the counter anion effect and the accompanying reactivity in cationic gold catalysis by
a gold affinity index and a hydrogen bonding basicity index,[7] which mainly addresses
the potential inhibition of the catalyst by the counter anion still coordinating. However,
a general study for the development of an efficient procedure to identify the gold
catalyst with the best catalytic activity, systematically involving both ligand and counter
anion, is still missing and highly desirable from an industrial view on homogeneous
gold catalysis. This encouraged us to shed light on the decisive factors for a strategical
approach for the catalyst screening in the course of the reaction optimization. It should
be noted that the ligand and counter anion effects are analyzed in this study, the
reasons for the observed effects are not part of this analysis but of an ongoing, more
extensive study.
Results and Discussion
As an entry point, the literature-known cyclopropanation of styrene by a propargyl
pivalate was chosen as a test reaction.[8] One equivalent of pivalate ([2-methylbut-3-
yn-2-yl pivalate] = 0.048 mmol/ml) was treated with four equivalents of freshly distilled
styrene and 0.5 – 0.05 mol% gold(I) complex in DCM at 25 °C for 15 h using
n-dodecane as internal standard (Scheme 1). We systematically varied ligand and
counter anion combinations of the gold(I) catalyst and detected the impact on the
catalytic activity. To exclude any “silver effects”[9] arising from in situ activation, we
isolated and purified a set of 24 gold(I) complexes of the type L-Au-X using NHC,
phosphine and phosphite ligands in combination with the three established counter
-
-
-
anions X = NTf2 , SbF6 and BF4 . In a few exceptions, it was not possible to isolate the
activated gold(I) complexes. In these cases, the silver salt was removed by filtration
through Celite before the reaction was started. The achieved turnovers (TOs) were
used to describe the catalyst efficiency and the stability of the catalytic system. As
shown in Figure 2, a remarkable impact of the counter anion on the gold catalysis was
observed.
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
Scheme 1. Cyclopropanation of styrene with a propargyl pivalate.
0.1 mol% IPrAuNTf2
0.2 mol% IPrAuSbF6
0.5 mol% IPrAuBF4
0.05 mol% TEDIIAuNTf2
0.1 mol% TEDIIAuSbF6
0.5 mol% TEDIIAuBF4
0.1 mol% Ph3PAuNTf2
0.5 mol% Ph3PAuSbF6
0.5 mol% Ph3PAuBF4
0.05 mol% (C6F5)3PAuNTf2
0.2 mol% (C6F5)3PAuSbF6
0.2 mol% (C6F5)3PAuBF4
0.1 mol% SPhosAuNTf2
0.2 mol% SPhosAuSbF6
0.5 mol% SPhosAuBF4
0.5 mol% BrettPhosAuNTf2
0.5 mol% BrettPhosAuSbF6
0.5 mol% BrettPhosAuBF4
0.1 mol% (CF3CH2O)3PAuNTf2
0.2 mol% (CF3CH2O)3PAuSbF6
0.5 mol% (CF3CH2O)3PAuBF4
0.05 mol% [[(CH3)3C]2C6H3O]3PAuNTf2
0.1 mol% [[(CH3)3C]2C6H3O]3PAuSbF6
0.5 mol% [[(CH3)3C]2C6H3O]3PAuBF4
0
200
400
600
800 1000 1200 1400 1600
Turnovers
Figure 2. Catalytic activity of selected gold(I) complexes.
Interestingly, for almost all tested ligands the reactivity order concerning the counter
-
anions was equivalent. In the case of BF4 , the catalytic reaction often was even
-
inhibited. Using the counter anion NTf2 in combination with various ligands always led
-
to the best result. Whereas, the counter anion SbF6 for almost every ligand has taken
second place in the examined ranking. Due to this result, it is not requisite to examine
the counter anions for each ligand, which is a tremendous simplification of the overall
screening procedure. The influence of the ligand was less pronounced, with the
exception of the bulky BrettPhos ligand which exhibited a drastic decrease of the TOs.
Based on these results, now a stronger focus was put on the role of the counter anion
-
in the subsequent experiments. A variety of counter anions, namely Cl-, NTf2 , OTf-,
-
-
SbF6 , BF4 and OTs- were selected. As ligands we choose an NHC, a phosphine and
a Buchwald ligand (namely IPr, PPh3 and SPhos) in combination with the mentioned
counter anions. As soon as the counter anion with the highest catalytic activity was
identified, a further optimization cycle was conducted with a larger pool of ligands
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
(Scheme 2). In Figure 3, a direct comparison of the common catalyst screening and
our simplified screening method divided into Screening A and Screening B is
visualized. In case of our investigated 22 ligands / 6 counter anions combination, a
holistic catalyst screening of the full ligand/counter anion (22 x 6) matrix requires 132
test reactions. Whereas, a pre-screening (Screening A) to determine the best of the 6
counter anions with the 3 initial ligands, followed by a screening (Screening B) of the
remaining 19 ligands in combination with the optimal counter anion from Screening A,
leads to the best catalyst within 3 x 6 + 19 = 37 experiments. This simplification
becomes possible as we observed the same trends with respect to the counter anions
for each ligand (see Figure 2). Hence, it is possible to reduce the workload by 72 %.
In principle, this amount of test reactions potentially could even be minimized by using
just one active ligand in Screening A.
Figure 3. Simplified screening method.
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
Scheme 2. Pool of ligands and complexes
To further support this approach, well-known and previously investigated reactions as
representatives of main reactivity patterns in gold catalysis were chosen (Scheme
3):[8a,10] Cyclopropanation (Equations 1a and 1b) as a probe for a possible substrate
dependence, the rearrangement of an allenylether (Equation 2), oxidative gold
catalysis using N-oxides (Equation 3), a hydroarylation (Equation 4) and an
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
alkylideneoxazoline synthesis (Equation 5) as representative for the formation of a
heterocycle were selected. All reactions were monitored by GC or 1H NMR techniques
which ensured an efficient analysis. Pre-screening of the reactions for reproduceable
conditions, involving solvent, concentration, temperature and internal standard were
conducted.
Scheme 3. Selected test reactions.
Cyclopropanation (Scheme 3, Equation 1a, 1b)
In the case of the cyclopropanation reaction a GC screening in DCM was conducted.
If a complete consumption of the starting material was observed within a reaction time
of 15 h a lower catalyst loading was used. Based on the new strategy, Screening A
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
(Figure 4) was applied. The suitability of an optimized catalyst to reactions of the same
reaction type but electronically different substrates was checked by the introduction a
chloro substituent (Equation 1b).
0.5 mol% 0.5 mol% IPrAuCl
0.5 mol% 0.5 mol% Ph3PAuCl
0.5 mol% 0.5 mol% SPhosAuCl
0.1 mol% 0.5 mol% IPrAuNTf2
0.1 mol% 0.5 mol% Ph3PAuNTf2
0.1 mol% 0.5 mol% SPhosAuNTf2
0.2 mol% 0.5 mol% IPrAuOTf
0.5 mol% 0.5 mol% Ph3PAuOTf
0.5 mol% 0.5 mol% SPhosAuOTf
0.2 mol% 0.5 mol% IPrAuSbF6
0.5 mol% 0.5 mol% Ph3PAuSbF6
0.2 mol% 0.5 mol% SPhosAuSbF6
0.5 mol% 0.5 mol% IPrAuBF4
0.5 mol% 0.5 mol% Ph3PAuBF4
0.5 mol% 0.5 mol% SPhosAuBF4
0.5 mol% 0.5 mol% IPrAuOTs
0.5 mol% 0.5 mol% Ph3PAuOTs
0.5 mol% 0.5 mol% SPhosAuOTs
0
200
400
600
800
1000
Turnovers
Figure 4. Counter anion effect with respect to the electronic nature of the substrate; (a,
blue) cyclopropanation of styrene by a propargyl pivalate; (b, red) cyclopropanation of
4-chlorostyrene by a propargyl pivalate.
Figure 4 shows a significant counter anion influence. In both cases, the best result was
-
-
observed with NTf2 . In comparison, the counter anions Cl-, BF4 and OTs- reached an
activity which in some cases was up to 90 % lower. Furthermore, an immense
substrate dependency was observed. In total, the catalyst performance for 4-
-
-
chlorostyrene (Figure 4b) was slightly better for using NTf2 instead of SbF6 as counter
anion. In comparison to Figure 4a, the choice of the counter anion for further
examinations is not explicit. Moreover, the turnovers compared to the cyclopropanation
with styrene (Figure 4a) are significantly reduced and in combination with the counter
-
anions Cl-, BF4 and OTs- no conversion was detected. As a next step, various ligands
-
were analyzed in combination with NTf2 as counter anion for both styrene derivatives
(Figure 5).
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
0.1 mol% 0.5 mol% IPrAuNTf2
0.1 mol% 0.5 mol% IPr*AuNTf2
0.1 mol% 0.5 mol% IMesAuNTf2
0.5 mol% 0.5 mol% SIPrAuNTf2
0.2 mol% 0.2 mol% NHC-Cy2AuNTf2
0.2 mol% 0.5 mol% NHC-tBu2AuNTf2
0.05 mol% 0.5 mol% TEDIIAuNTf2
0.1 mol% 0.5 mol% Ph3PAuNTf2
0.5 mol% 0.5 mol% Cy3PAuNTf2
0.5 mol% 0.5 mol% tBu3PAuNTf2
0.2 mol% 0.5 mol% Mes3PAuNTf2
0.05 mol% 0.2 mol% (C6F5)3PAuNTf2
0.5 mol% 0.5 mol% CatacXiumAuNTf2
0.5 mol% 0.5 mol% BrettPhosAuNTf2
0.5 mol% 0.5 mol% XPhosAuNTf2
0.1 mol% 0.5 mol% SPhosAuNTf2
0.05 mol% 0.5 mol%
[[(CH3)3C]2C6H3O]3PAuNTf2
0.1 mol% 0.5 mol% (CF3CH2O)3PAuNTf2
0.5 mol% 0.5 mol% CAAC-CyclohexylAuNTf2
0.1 mol% 0.5 mol% AuCl
0.05 mol% 0.5 mol% AuCl3
0.1 mol% 0.2 mol% Dichloro(2-pyridinecarboxylato)gold
0
200 400 600 800 1000 1200 1400 1600 1800
Turnovers
Figure 5. Direct comparison of the ligand influence concerning substrate dependency;
(a, blue) cyclopropanation of styrene with a propargyl pivalate; (b, red)
cyclopropanation of 4-chlorostyrene with a propargyl pivalate.
A strong substrate dependency within the same reaction type was also observed for
this test. In case of styrene (Figure 5a), the (C6F5)3PAuNTf2 and
[((CH3)3C)2C6H3O]3PAuNTf2 catalysts achieved the best turnover numbers while for 4-
chlorostyrene (Figure 5b) AuCl3 showed the highest catalytic activity.
In case of styrene (Figure 5a), the (C6F5)3PAuNTf2 (TON = 1627) and
[((CH3)3C)2C6H3O]3PAuNTf2 (TON = 1680) catalysts achieved the best turnover
numbers while for 4-chlorostyrene (Figure 5b) dichloro(2-pyridinecarboxylato)gold
(TON = 460) showed the highest catalytic activity. In comparison, in the literature for
the cyclopropanation of styrene with a pivalate the in situ activated gold(I) catalyst
Ph3PAuCl/ AgSbF6 achieved only 15 turnovers.[8a] 100 turnovers were reported by
Alcarazo and co-workers using a cyclopropenylylidene-stabilized dialkyl phosphenium
cation as ligand.[8b] The corresponding conversion of 4-chlorostyrene has not been
reported in the literature.
1,3 Rearrangement of an allenylether (Scheme 3, Equation 2)
On the GC columns available in the group, the starting material and product had the
same retention time. Thus detection by gas chromatography was not possible and the
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
1
reaction was monitored by H NMR using 1,4-dinitrobenzene as internal standard
(Figure 6). Within the examined test series, a limited selectivity of the reaction was
monitored for all reactions in Screening A. Especially, the combination of the IPr ligand
-
with different counter anions, with exception of SbF6 , exclusively led to hydrolysis[10a]
-
of the allenylether. Within the three ligand systems, the counter anion SbF6 provided
the best results with respect to the turnovers as well as the selectivity of the reaction.
Due to this fact, further examinations concerning ligands were conducted with the
-
counter anion SbF6 (Figure 7).
IPrAuCl
Ph3PAuCl
SPhosAuCl
IPrAuNTf2
Ph3PAuNTf2
SPhosAuNTf2
IPrAuOTf
Ph3PAuOTf
SPhosAuOTf
IPrAuSbF6
Ph3PAuSbF6
SPhosAuSbF6
IPrAuBF4
Ph3PAuBF4
SPhosAuBF4
IPrAuOTs
Ph3PAuOTs
SPhosAuOTs
0
20
40
60
80
100
120
140
160
Turnovers
Figure 6. Counter anion effect on the 1,3 rearrangement of an allenylether.
IPrAuSbF6
IPr*AuSbF6
IMesAuSbF6
SIPrAuSbF6
NHC-Cy2AuSbF6
NHC-tBu2AuSbF6
TEDIIAuSbF6
Ph3PAuSbF6
Cy3PAuSbF6
tBu3PAuSbF6
Mes3PAuSbF6
(C6F5)3PAuSbF6
CatacXiumAuSbF6
BrettPhosAuSbF6
XPhosAuSbF6
SPhosAuSbF6
[[(CH3)3C]2C6H3O]3PAuSbF6
(CF3CH2O)3PAuSbF6
CAAC-CyclohexylAuSbF6
AuCl
AuCl3
Dichloro(2-pyridinecarboxylato)gold
0
20
40
60
80
100
120
140
160
180
Turnovers
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
Figure 7. Ligand influence on the 1,3 rearrangement of an allenylether.
The best turnover numbers and selectivities were achieved with the investigated
phosphite ligands, closely followed by the catalysts (C6F5)3PAuSbF6 and CAAC-
Cyclohexyl-AuSbF6. No reaction was observed by using AuCl or gold(III) complexes.
In the literature only hydrolysis was observed with this substrate, the authors used
Ph3PAuCl in combination with the silver salts AgNTf2 and AgSbF6 for this substrate.[10a]
Our screening for the first time led to a catalyst that is able to induce the desired
rearrangement.
Oxidative gold catalysis (Scheme 3, Equation 3)
Because of the extended reaction times, the reaction solution was analyzed after 15 h,
40 h, 7 d and 14 d by gas chromatography. Like in the other examples, the turnovers
are depending on the counter anions (Figure 8). In case of the counter anions OTs-
and Cl- no reaction was detected with any of the investigated ligands. The only
exception of the reactivity order was observed in the case of SPhosAuOTf. For this
ligand other counter anions all delivered either no reaction or poor selectivity. Because
of the unselective reaction of SPhosAuBF4 and the slightly decreased turnover of
-
-
Ph3PAuBF4 in comparison to its NTf2 analogues, the counter anion NTf2 was chosen
for further examinations (Figure 9).
IPrAuCl
Ph3PAuCl
SPhosAuCl
IPrAuNTf2
Ph3PAuNTf2
SPhosAuNTf2
IPrAuOTf
Ph3PAuOTf
SPhosAuOTf
IPrAuSbF6
Ph3PAuSbF6
SPhosAuSbF6
IPrAuBF4
Ph3PAuBF4
not selective
SPhosAuBF4
IPrAuOTs
Ph3PAuOTs
SPhosAuOTs
0
2
4
6
8
10
12
14
16
Turnovers
Figure 8. Counter anion influence on an oxidative gold catalysis.
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
In Figure 9, the strong ligand effect on the investigated oxidative gold catalysis is
illustrated. The Buchwald ligand BrettPhos gained an almost complete conversion
within the first 15 h. Only the ligand XPhos achieved an almost comparable result but
within an extended reaction time of 7 d. Within the monitored reaction time of 14 d
phosphites, the CAAC-Cyclohexyl, SPhos, (C6F5)3P as well as the gold(III) complexes
showed almost no or no reaction.
IPrAuNTf2
IPr*AuNTf2
not selective
IMesAuNTf2
SIPrAuNTf2
NHC-Cy2AuNTf2
NHC-tBu2AuNTf2
TEDIIAuNTf2
Ph3PAuNTf2
Cy3PAuNTf2
tBu3PAuNTf2
Mes3PAuNTf2
(C6F5)3PAuNTf2
CatacXiumAuNTf2
not selective
BrettPhosAuNTf2
XPhosAuNTf2
SPhosAuNTf2
[[(CH3)3C]2C6H3O]3PAuNTf2
(CF3CH2O)3PAuNTf2
CAAC-CyclohexylAuNTf2
AuCl
AuCl3
Dichloro(2-pyridinecarboxylato)gold
0
5
10
15
20
Turnovers
Figure 9. Ligand influence on an oxidative gold catalysis.
The Buchwald ligand BrettPhos (20 turnovers) achieved an almost complete
conversion within the first 15 h. Only the ligand XPhos (18 turnovers) achieved an
almost comparable result but within an extended reaction time of 7 d. Within the
monitored reaction time of 14 d phosphites, the CAAC-Cyclohexyl, SPhos, (C6F5)3P as
well as the gold(III) complexes showed a very low or no conversion. In comparison,
Zhang and co-workers achieved an almost similar turnover using Me4tBuXPhosAuNTf2
(17 turnovers), however, the reaction times we observed are much higher than the
reaction times claimed in the literature.[10b]
Hydroarylation (Scheme 3, Equation 4)
An immense counter anion effect was observed again (Figure 10). The counter anions
-
-
BF4 , OTf-, NTf2 and Cl- show similar reaction patterns concerning the investigated
gold(I) complexes. The best results for each ligand were obtained by far using the
-
counter anion SbF6 .
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
IPrAuCl
Ph3PAuCl
SPhosAuCl
IPrAuNTf2
Ph3PAuNTf2
SPhosAuNTf2
IPrAuOTf
Ph3PAuOTf
SPhosAuOTf
IPrAuSbF6
Ph3PAuSbF6
SPhosAuSbF6
IPrAuBF4
Ph3PAuBF4
SPhosAuBF4
IPrAuOTs
Ph3PAuOTs
SPhosAuOTs
0
2
4
6
8
Turnovers
Figure 10. Counter anion influence on the hydroarylation reaction.
Based on a ligand pre-screening by TLC and GC control (see Supporting Information
for further details), only selected ligands were analyzed in a further series of
experiments. Decomposition of the starting material was observed for most of the
investigated ligands. The best result by far was obtained with (C6F5)3PAuSbF6 (Figure
11).
IPr*AuSbF6
IMesAuSbF6
TEDIIAuSbF6
(C6F5)3PAuSbF6
[[(CH3)3C]2C6H3O]3PAuSbF6
(CF3CH2O)3PAuSbF6
0
10
20
30
40
50
60
70
Turnovers
Figure 11. Ligand influence on the hydroarylation reaction.
Again, here we obtained by far the best result reported so far, (C6F5)3PAuSbF6 (63
turnovers, Figure 11). The best catalyst known in the literature only achieved 49
turnovers, this was reported by Alcarazo and co-workers using a polycationic
ligand.[10c]
Synthesis of alkylideneoxazoline (Scheme 3, Equation 5)
For the cyclization of propargylamides after a reaction time of 74 h, the TOs show an
enhanced dependence on the counter anions. However, the ligand influence is not
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
insignificant (Figure 12). Noticeable, in this case no convergence of the results was
observed and in this case the best counter anion changed for the applied ligands. In
-
sum, the best catalytic activity was achieved by the counter anion NTf2 . Due to this,
-
NTf2 was used for the following examinations concerning the ligands (Figure 13).
IPrAuCl
Ph3PAuCl
SPhosAuCl
IPrAuNTf2
Ph3PAuNTf2
SPhosAuNTf2
IPrAuOTf
Ph3PAuOTf
SPhosAuOTf
IPrAuSbF6
Ph3PAuSbF6
SPhosAuSbF6
IPrAuBF4
Ph3PAuBF4
SPhosAuBF4
IPrAuOTs
Ph3PAuOTs
SPhosAuOTs
0
200
400
600
800
1000
Turnovers
Figure 12. Counter anion influence on the synthesis of alkylideneoxazoline.
Due to the high catalytic activity, the reaction time was decreased from 74 h to 22 h.
The results of the best ligands are shown in Figure 13. The examinations show a highly
selective reaction, whereby using gold(III) complexes afforded an isomerization of the
gained oxazoline to oxazol after an extended time period.[11] However, within a
decreased reaction time of 22 h gold(III) complexes as well as Ph3PAuNTf2 turned out
to be the best catalysts and at that stage no isomerization was monitored for the
gold(III) species.
IPrAuNTf2
IPr*AuNTf2
NHC-tBu2AuNTf2
Ph3PAuNTf2
tBu3PAuNTf2
(C6F5)3PAuNTf2
SPhosAuNTf2
[[(CH3)3C]2C6H3O]3PAuNTf2
(CF3CH2O)3PAuNTf2
AuCl3
Dichloro(2-pyridinecarboxylato)gold
0
200
400
600
800
1000
Turnovers
Figure 13. Ligand influence on the synthesis of alkylideneoxazoline.
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
Again we want to put our results into context. Within a decreased reaction time of only
22 h gold(III) complexes (1000 turnovers) as well as Ph3PAuNTf2 (1000 turnovers)
turned out to be the best catalysts and no isomerization was monitored for the gold(III)
catalysts. Probert and co-workers achieved only 50 turnovers using a modified
KITPhos ligand in combination with AgOTf as the silver salt.[10e] Hashmi and co-
workers used a by AgPF6 for the in situ activation of a gold(I) catalyst based on a
hydrazino amino acyclic carbene and achieved only 100 turnovers.[10f,10g]
Conclusion
An intense screening of key reactivity types from various fields of gold catalysis,
concerning the ligand and the counter anion of gold catalysts, was conducted. For each
test reaction the counter anion significantly affected the catalytic activity. This counter
anion influence was mostly more pronounced than the corresponding influence of the
ligand. Moreover, for nearly every substrate one or more counter anion showed no or
only minor consumption of the substrate. It became obvious that the counter anion
influence is still underestimated in experimental homogeneous gold catalysis. In almost
all cases the best counter anion for one gold catalyst showed also the highest activity
for all investigated ligands; this allowed the establishment of a simplified strategical
screening procedure. In a first Screening A, we suggest to use a broad set of
established silver salts of the counter anions with a limited set of benchmark ligands
for an initial identification of the best counter anion. In a second step, Screening B,
we advise further examinations concerning a large pool of ligands in combination with
the superior counter anion from Screening A. By following this procedure, the
theoretical number of screening experiments which would be necessary to identify the
optimal gold catalyst, can be significantly reduced. By means of the cyclopropanation
of styrenes by a propargylic pivalate, it was shown that a minimal variation of the
substrate leads to significantly different reactivities concerning the counter anion as
well as the ligand. Hence, which is no surprise, no general perfect catalyst for a specific
reaction exists.
Experimental Section
General remarks
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
Chemicals were, if not noted otherwise, used from the stock of the University of
Heidelberg or were bought from commercial suppliers such as Sigma-Aldrich, Strem
and Carbolution. Deuterated solvents were purchased from Euriso-Top. The
experiments were carried out in standard laboratory glassware.
NMR (Nuclear magnetic resonance) spectra were recorded at room temperature on
Bruker Avance III-300 or Avance DRX-300. 1H NMR spectra were calibrated using the
residual solvent signal (CD2Cl2: 5.32 ppm).
Gas Chromatography (GC) was processed on HP 58090 SERIES II with a HP 1
column. Nitrogen was used as the carrier gas.
Analytical thin layer chromatography (TLC) was carried out on pre-coated
aluminum sheets provided by Macherey-Nagel ALUGRAM® Xtra SIL G/UV254.
Components were visualized by irradiation under UV light (254 nm).
General procedures
All substrates were isolated according to literature in good to excellent yields.[1-5]
General procedure 1 (GP 1) – GC screening; cyclopropanation of styrene with pivalate
4.6 μl (0.025 mmol; 1 equiv) of 2-methylbut-3-yn-2-yl pivalate was dissolved in 0.5 ml
DCM. Afterwards, 11.5 μl (R = H), 12.0 μl (R = Cl) (0.100 mmol; 1 equiv) of freshly
distilled styrene, 5.7 μl (0.025 mmol; 1 equiv) of n-dodecane and 0.5 mol%
(0.125 μmol, 0.005 equiv) of gold catalyst were added to the reaction mixture and the
reaction was stirred at room temperature. After a reaction time of 15 h, the gold catalyst
was removed via filtration through Silica gel (petroleum ether / ethyl acetate, 1:1) and
the reaction sample was analyzed using GC. If an substrate consumption of 100 %
was observed within a reaction time of 15 h, the reaction was repeated with a lower
catalyst loading.
General procedure 2 (GP 2) – 1H NMR screening; 1,3 rearrangement of an allenylether
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
In a NMR tube, 4.0 μl (0.025 mmol; 1 equiv) of 1-methoxy-4-((propa-1,2-dien-1-
yloxy)methyl)benzene and 4.2 mg (0.025 mmol; 1 equiv) of 1,4-dinitrobenzene was
dissolved in 0.5 ml deuterated DCM. Afterwards, the reaction mixture was cooled to
0 °C and 0.5 mol% (0.125 μmol, 0.005 equiv) of gold catalyst were added. After a
reaction time of 1 h at 0 °C, the reaction was analyzed by 1H NMR.
General procedure 3 (GP 3) – GC screening; oxidative gold catalysis using an N-
oxide
9.3 μl (0.050 mmol; 1 equiv) of 1-(tert-butyl)-4-(prop-2-yn-1-yloxy)benzene, 22.2 mg
(0.075 mmol, 1.5 equiv) of diethyl-2,6-diethylpyridin-3,5-dicarboxylate-N-oxide and
11.3 μl (0.050 mmol; 1 equiv) of n-dodecane were dissolved in 1.0 ml DCE. Afterwards,
5 mol% (0.0025 mmol, 0.05 equiv) of gold catalyst were added to the reaction mixture
and the reaction was stirred at room temperature. Because of the extended reaction
times, the reaction solution was analyzed after 15 h, 40 h, 7 d and 14 d. Therefore, the
gold catalyst was removed via filtration through Silica gel (petroleum ether / ethyl
acetate, 1:1) and the reaction sample was monitored using GC.
General procedure 4 (GP 4) – GC screening; hydroarylation
Investigation of the counter anion effect
10 mg (0.048 mmol; 1 equiv) of 2-ethynyl-2',6-dimethyl-1,1'-biphenyl and 11.0 μl
(0.048 mmol; 1 equiv) of n-dodecane were dissolved in 0.97 ml DCM. Afterwards,
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10.1002/adsc.201800233
Advanced Synthesis & Catalysis
2 mol% (0.97 μmol, 0.02 equiv) of gold catalyst were added to the reaction mixture and
the reaction was stirred at room temperature for 4 d. The gold catalyst was removed
via filtration through Silica gel (petroleum ether / ethyl acetate, 1:1) and the reaction
sample was monitored using GC.
Acknowledgements
Innovam is co-financed by the Heidelberg University and Umicore AG & Co. KG.
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