The role of silver additives in gold-mediated C-H functionalisation

Article abstract of DOI:10.3762/bjoc.7.102

The role of silver additives is examined in the context of gold-mediated functionalisation of aromatic C-H bonds. Doubt is cast on the commonly cited route of halide abstraction from gold and evidence of substrate activation is given.

Full text of DOI:10.3762/bjoc.7.102

The role of silver additives in gold-mediated
C–H functionalisation
Scott R. Patrick, Ine I. F. Boogaerts, Sylvain Gaillard, Alexandra M. Z. Slawin
and Steven P. Nolan*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 892–896.
EaStCHEM School of Chemistry, University of St Andrews, North
Haugh, St Andrews, KY16 9ST, UK
doi:10.3762/bjoc.7.102
Received: 18 April 2011
Accepted: 09 June 2011
Published: 01 July 2011
Email:
Scott R. Patrick - srp3@st-andrews.ac.uk; Ine I. F. Boogaerts -
ib51@st-andrews.ac.uk; Sylvain Gaillard - sg210@st-andrews.ac.uk;
Alexandra M. Z. Slawin - amzs@st-andrews.ac.uk; Steven P. Nolan* -
snolan@st-andrews.ac.uk
This article is part of the Thematic Series "Gold catalysis for organic
synthesis".
* Corresponding author
Guest Editor: F. D. Toste
Keywords:
© 2011 Patrick et al; licensee Beilstein-Institut.
License and terms: see end of document.
C–H functionalisation; gold catalyst; halide abstraction; N-heterocyclic
carbene; silver salt; substrate activation
Abstract
The role of silver additives is examined in the context of gold-mediated functionalisation of aromatic C–H bonds. Doubt is cast on
the commonly cited route of halide abstraction from gold and evidence of substrate activation is given.
Introduction
The use of gold in homogeneous catalysis is an area where The reactivity profile of 1 appears linked to bond acidity, and
fascinating advances have been realised in the last few years was found to functionalise selectively the most electron-defi-
[1-4]. One of these discoveries has focused on the possibility of cient C–H bond in a substrate. Unfortunately, the reactivity of 1
using gold in metalation reactions [5-8] directly leading to was limited to bonds with a pKa value below 30.4 [12].
organogold complexes. The further use of organogold
complexes bearing N-heterocyclic carbenes (NHC) [9,10] as Current gold research has shown that silver salts can not only
supporting ligands has enabled the isolation of a “golden improve reaction times and yields [13,14], but also allow the
synthon”, [Au(OH)(IPr)] 1 (IPr = 1,3-bis(2,6-diisopropyl- C–H functionalisation of previously unreactive substrates.
phenyl)imidazol-2-ylidene), that is able to participate in metala- Larrosa has recently disclosed a mild methodology for the
tion reactions with aromatic C–H bonds (Scheme 1) [11].
Au(I)-mediated C–H functionalisation of 1,3,5-trifluoroben-
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Beilstein J. Org. Chem. 2011, 7, 892–896.
Scheme 1: Silver-free C–H functionalisation using [Au(OH)(IPr)].
zene (2, pKa DMSO 31.5 [15]) using a mixture of reagents and it was the only additive used, no reaction took place. These
additives (Scheme 2) [16]. The observation of a high kinetic results clearly eliminate the involvement of K2CO3 in direct
isotope effect is suggestive of a concerted metalation–deproto- deprotonation of the substrate [18]. Potassium carbonate reacts
nation mechanism, as first suggested for Pd(II) complexes, in with pivalic acid to form KOPiv, leading to improved yields in
which a pivalate ligand behaves as a proton acceptor via a six- the Larrosa methodology. However, this practice was not neces-
membered transition state [17]. However, addition via a tran- sary in our work and the salt did not appear to have any other
sient Au(III) hydride would also be consistent with these obser- role in the mechanism. Further reactions did not utilise K2CO3.
vations.
The reaction between [AuCl(IPr)], 2 and Ag2O yielded no pro-
Results and Discussion
duct. A stoichiometric addition of pivalic acid was required for
We became interested in understanding the mechanistic details the reaction to proceed. The acid was believed to generate the
of this transformation by identifying the role of the individual reactive intermediate 3 [Au(OPiv)(IPr)] (OPiv = (CH3)3CCO2)
components. Reactions were performed between individual (Figure 1). To verify this hypothesis, the well-defined complex
reagents and the formation of products was observed by [19] was used in test reactions following the earlier conditions.
1H NMR spectroscopy. Silver(I) oxide and potassium carbonate Complex 3 reacted with 2 in conjunction with Ag2O and gave
both reacted with pivalic acid to form metal pivalates after stir- complete conversion to 4 [Au(C6H2F3)(IPr)]. This strongly
ring in toluene at 50 °C for 20 h. Potassium carbonate did not suggests that complex 3 is indeed an intermediate. However, the
interact directly with the aryl substrate after stirring in DMF at use of a silver salt was essential for the reaction to proceed.
50 °C for 24 h. A stoichiometric reaction between Ag2O and the
substrate displayed substitution of one of the protons. However, The silver salt was suspected of abstracting the halide from
deuterium incorporation experiments were unsuccessful and [AuCl(IPr)] to generate a possibly active cationic gold(I)
mass spectrometry on the product was inconclusive.
species [20]. To test this hypothesis, the well-defined cationic
complex [(IPrAu+)(NCMe)][BF4-] [21] was reacted with 2 in
The reaction depicted in Scheme 2 was performed using a the absence of other reagents. No product was observed. Subse-
neutral gold(I)-NHC complex. The reaction time was extended quent test reactions were performed using 1 (Table 1, entries
to 20 h in order to obtain optimal results. A reaction involving 1–3), thus eliminating the possible in situ formation of cationic
[AuCl(IPr)] proceeded with full conversion to product with all gold(I). The reaction proved successful in the presence of
additives/reagents present. The removal of potassium carbonate Ag2O, suggesting that silver does not generate cationic gold.
from the reaction had no detrimental effect. Additionally, when The reaction with pivalic acid gave a better conversion, indi-
Scheme 2: C–H functionalisation of 2 using gold-phosphine complexes and a silver additive.
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Beilstein J. Org. Chem. 2011, 7, 892–896.
cating that the gold proceeded via complex 3. Further reactions
used 1 as the gold species and no longer included PivOH.
The stoichiometric dependence of the silver salt was then exam-
ined. Both 0.50 and 0.25 equivalents of Ag2O gave poor
conversions to the product (entries 4 and 5) and further reducing
the loading to 0.1 equivalents stopped the reaction entirely
(entry 6).
A range of silver salts was compared in reactions involving 1
and 2. Both AgF and AgOAc gave full conversion to product
(entries 7 and 8), while the nature of the silver counter ion led
reactivity to decrease in the order Ag2O > AgI > AgO, AgBF4,
AgCl > Ag2CO3, AgOCOCF3 > AgNO3 > AgBr. Electronic
effects can explain the general reactivity-decreasing trend on
going from AgF to AgBr, but steric factors must also be consid-
ered to rationalise the anomalous activity of AgI. The Lewis
acidity of the silver salts may contribute to initiate the reaction
[22], but unsuccessful reactions using Al2O3, AlCl3, Cu2O or
ZnBr2 proved otherwise. The existence of a transient anion
exchange between the gold (AuX) and the silver salt (AgY)
may generate the active “AuY” complex. However, this was
disproved by the successful reaction using AgCl. This would
implicate [AuCl(IPr)] as the possible active species. This has
Figure 1: X-ray structure of [Au(OPiv)(IPr)] 3. Thermal ellipsoids are
shown at the 50% probability level. H atoms are omitted for clarity.
Selected bond distances (Å) and angles (°) for 3: Au1–C1 1.978(5),
Au1–O1 2.048(4), O1–C2 1.299(8), C2–O2 1.231(9), C1–Au1–O1
178.0(2), Au1–O1–C2 120.7(4), O1–C2–O2 124.6(6).
Table 1: C–H functionalisation of 2 using 1.a
Entry
AgY
Additive
Conversionb (%)
1
Ag2O
Ag2O
-
-
38
100
0
2
PivOH
3
PivOH
4c
5d
6e
7
Ag2O
Ag2O
Ag2O
AgF
-
-
-
-
-
15
11
0
100
100
8
AgOAc
aUnless otherwise noted, all reactions were carried out with 1 (1 equiv), 2 (4.5 equiv), salt (1.5 equiv) and additive (2.5 equiv) in a 0.2 M DMF solution.
bConversion to product was determined by 1H NMR analysis relative to 1. cAgY (0.5 equiv) was used. dAgY (0.25 equiv) was used. eAgY (0.1 equiv)
was used.
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Beilstein J. Org. Chem. 2011, 7, 892–896.
already been discounted since it was shown to be unreactive in to facilitate the reaction. The reaction was shown to require
the model C–H bond functionalisation reaction.
stoichiometric amounts of the silver salt. The failed reaction of
a cationic gold species hints that the silver salt has a role other
To complete the examination of possibly important parameters than abstracting halides. The successful reactions of 1 and 3,
enabling the reaction, the role of solvents was investigated. which cannot be dissociated by silver salts, reinforce this idea.
Solvent screening showed that the reaction could proceed in The choice of silver salt is very important, and has been shown
THF (59% conversion), DMF (38%), toluene (35%), 1,4- to widely influence the conversion achieved. The high electro-
dioxane (21%) and poorly in cyclopentyl methyl ether (CPME) negativity of the silver counter ion is of great importance.
(3%). The conversions do not mirror the polarity of the solvents Finally, evidence of an interaction between silver salts and the
and the silver salts were sparingly soluble in every solvent substrate suggests that silver activates the aryl C–H bond and is
tested [23].
then implicated in a transmetalation reaction with gold to
provide the product. The value of silver additives in catalytic
As the functionalisation of C–H bonds was now found possible carboxylation of C–H bonds was then illustrated in the forma-
in the presence of silver additives, we reasoned that a test of the tion of 2,4,6-trifluorobenzoic acid, which was hitherto unattain-
observation was to carry out a carboxylation reaction [12] with able by gold(I)-catalysed carboxylation using catalyst 1 alone.
substrate 2 using catalyst 1 under optimised carboxylation This may provide a method to increase the range of C–H bonds
conditions (Scheme 3).
amenable to functionalisation through gold-mediated carboxyla-
tion. Studies aimed at examining the extent of this effect are
ongoing in our laboratories.
Supporting Information
Supporting Information File 1
Detailed experimental procedures for the synthesis of
complexes 3–5.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-102-S1.pdf]
Scheme 3: Carboxylation of 2 using 1 and Ag2O.
The general procedure employed 2, 1 (3 mol %), Ag2O
(3 mol %) and three equivalents of potassium hydroxide. Grati-
fyingly, whereas a reaction in the absence of silver leads to no
carboxylation product, the addition of silver leads to formation
of 2,4,6-trifluorobenzoic acid (5). The use of a stoichiometric
amount of Ag2O results in aggregation of the reagents that
seemingly affects mass transport of CO2 and halts the reaction.
However, the catalytic use of Ag2O gave a 22% isolated yield
of 5. This observation clearly shows that silver can have a posi-
tive role in the carboxylation of C–H bonds.
Acknowledgements
We are grateful to EPSRC and ERC (Advanced Researcher
Award (FUNCAT) to SPN) for funding. SPN is a Royal
Society-Wolfson Research Merit Award holder.
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