Oxidant-Free Au(I)-Catalyzed Halide Exchange and Csp2-O Bond Forming Reactions

Article abstract of DOI:10.1021/jacs.5b08756

Au has been demonstrated to mediate a number of organic transformations through the utilization of its π Lewis acid character, Au(I)/Au(III) redox properties or a combination of both. As a result of the high oxidation potential of the Au(I)/Au(III) couple, redox catalysis involving Au typically requires the use of a strong external oxidant. This study demonstrates unusual external oxidant-free Au(I)-catalyzed halide exchange (including fluorination) and C_sp2-O bond formation reactions utilizing a model aryl halide macrocyclic substrate. Additionally, the halide exchange and C_sp2-O coupling reactivity could also be extrapolated to substrates bearing a single chelating group, providing further insight into the reaction mechanism. This work provides the first examples of external oxidant-free Au(I)-catalyzed carbon-heteroatom cross-coupling reactions.

Full text of DOI:10.1021/jacs.5b08756

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Article
Oxidant-Free Au(I)-Catalyzed Halide
sp2
Exchange and C-O Bond Forming Reactions
Jordi Serra, Christopher J Whiteoak, Ferran Acuña-Parés,
Marc Font, Josep M. Luis, Julio Lloret Fillol, and Xavi Ribas
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08756 • Publication Date (Web): 23 Sep 2015
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Journal of the American Chemical Society
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Oxidant-Free Au(I)-Catalyzed Halide Exchange and Csp2-O Bond
Forming Reactions
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Jordi Serra,1 Christopher J. Whiteoak,1 Ferran Acuña-Parés,1 Marc Font,1 Josep M. Luis,1 Julio Lloret-
Fillol1,2 and Xavi Ribas1,*
1 Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Campus de Montilivi, E-
17071 Girona, Catalonia (Spain).
2 Current address: Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Catalonia (Spain)
Supporting Information Placeholder
ABSTRACT: Au has been demonstrated to mediate a number of organic transformations through the utilization of its π Lewis acid
character, Au(I)/Au(III) redox properties or a combination of both. As a result of the high oxidation potential of the Au(I)/Au(III)
couple, redox catalysis involving Au typically requires the use of a strong external oxidant. This study demonstrates unusual exter-
nal oxidant-free Au(I)-catalyzed halide exchange (including fluorination) and Csp2-O bond formation reactions utilizing a model aryl
halide macrocyclic substrate. Additionally, the halide exchange and Csp2-O coupling reactivity could also be extrapolated to sub-
strates bearing a single chelating group, providing further insight into the reaction mechanism. This work provides the first exam-
ples of external oxidant-free Au(I)-catalyzed carbon-heteroatom cross-coupling reactions.
Introduction. Metal-mediated transformations in organic syn-
thesis have revolutionized the design of retro-synthetic strate-
gies for the preparation of new organic compounds.1-2 Amongst
these strategies, carbon–carbon (C-C) and carbon–heteroatom
(C-X) forming cross-coupling reactions mediated by Pd and
Cu have become the most established options.3-8,9-12 Neverthe-
less, the discovery of new methodologies involving other tran-
sition metals with the possibility of providing new selectivities
is highly desirable. Recently, during screening of the redox
chemistry of coinage metals with a model aryl macrocyclic
ligand we have provided experimental evidence regarding the
unexpected feasibility of Ag(I)/Ag(III) two-electron redox cy-
Scheme 1. Previously reported M(I) (M = Cu or Ag) catalyzed
cles in C-C and C-heteroatom cross-coupling catalysis,13 oper-
halide exchange reactions in model aryl halide macrocyclic sub-
ating analogously to Cu(I)/Cu(III) catalysis (Scheme 1).14-15 In
strates.
contrast to the other coinage metals, Au-catalyzed cross-
The viability of the oxidative addition of aryl halides at Au(I)
coupling catalysis has only been observed in the presence of
has recently attracted renewed interest, particularly in work
external oxidants.16-20 This difference in reactivity is due to the
reported by Bourissou and co-workers whereby the crystal
high oxidation potential of the Au(I)/Au(III) redox couple (E0
structures of aryl-Au(III)-I oxidative addition products have
= + 1.41 V in water),21 and, as a result, Au(I)-catalyzed C-C
been reported.35 These compounds are reported to be extremely
bond forming reactions utilizing the π Lewis acid properties of
stable and no further reactivity was observed. In addition,,
Au are more common.22-29
Toste recently reported Au(I) oxidative addition using
biphenylene to obtain [IPrAu(III)(biphenyl)]+, where after its
The engagement of Au(I) catalysis in aryl halide oxidative
Lewis acid properties are further exploited.36 Reductive elimi-
addition has been a matter of controversy over the past few
years. In 2007 Corma and co-workers reported what they con-
sidered to be the first example of Au(I)-catalyzed Sonogashira
couplings using aryl iodides without the need for an external
oxidant,30 but in 2010 Espinet, Echavarren and co-workers
provided evidence on the unlikelihood that these Au(I)-
catalyzed Sonogashira coupling reactions proceeded in the
absence of Pd impurities.31-32 Around the same time, Lambert
and co-workers provided further evidence that the activity ob-
served in these Au-catalyzed Sonogashira couplings was a
consequence of the presence of Au nanoparticles.33 The latter
observation was also later reported by Corma and co-workers
in 2011.34
nation from Au(III) for C-C bond formation has long been
known, particularly from the groups of Kochi, Tobias and Vin-
cent, reporting reductive eliminations from dialkyl-Au(III)
complexes, although not in a catalytic fashion.37,38,39,40 More
recently, Toste and co-workers have also described an extreme-
ly fast reductive elimination from Au(III) complexes forming
biaryl compounds.41 These oxidative addition and reductive
elimination steps have been combined in a stepwise stoichio-
metric intramolecular Au-mediated allylation of arylboronic
acids proceeding through an isolable Au(III) intermediate in-
dicating the feasibility of these conversions.36, 42-43
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aryl iodide when using soluble nBu4NBr or nBu4NI, respec-
tively.
Inspired by these reports we decided to investigate the possi-
1
2
3
4
bility of external oxidant-free Au(I)-catalyzed cross-coupling
reactions using our model systems and to study the intrinsic
differences of Au reactivity compared to the previously report-
ed two-electron redox catalysis with Ag and Cu.8, 13, 15
Table 1. Catalytic halide exchange reactions with L1-X in
CD3CN under N2.a
5
6
7
Results and Discussion.
Au(I)-catalyzed halide exchange in aryl-X model sub-
strates (X = Cl, Br, I). In analogy to our previous works on
Ag and Cu based halide exchange reactions, we first attempted
a stoichiometric reaction by adding one equivalent of a Au(I)
source, [AuCl(SMe2)], to a CD3CN solution of L1-Br (1 equiv)
in, whereby we observed the immediate formation of a precipi-
tate as well as a change in the color of the solution to pale vio-
let, indicating the decomposition of the Au(I) precursor to
Au(0) in the form of Au nanoparticles. This result suggested
that the soft nature of the Au(I) cation could not be stabilized
by the secondary and tertiary amines of the model aryl halide
macrocycle as with our previous examples using Cu and Ag.
Also, we realized that Au(I) was prone to disproportionation to
form metallic Au, therefore a strongly coordinating ligand
should be used to stabilize Au(I) in solution to avoid this det-
rimental side reaction.
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Yield
T
(oC)
Entry
L1-X
L1-I
MY (eq.)
Au(I) (10 mol%)
t (h)
L1-Y
(%)b
>99
1
2
AuCl(PPh3)
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
40
40
40
40
40
40
40
40
40
40
40
40
70
70
70
70
70
70
70
70
70
70
70
70
48
48
6
97
>99c
Bu4N-Cl
(2)
3
4
48
48
48
30
48
60
60
12
60
18
8
2
5
AuCl(PPh3)
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
5 (94)d
9 (96)d
15 (97)d
0 (36)d
98
6
NaBr
(10)
7
8
9
L1-Br
AuCl(PPh3)
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
Bu4N-Cl
(2)
We decided to first investigate the potential for catalytic halide
exchange in the aryl halide macrocycle mediated by
[AuCl(PPh3)]. Initially we focused on L1-I in the presence of a
catalytic amount of [AuCl(PPh3)] (10 mol%) and 2 equivalents
of tetrabutylammonium chloride (nBu4N-Cl) in CD3CN and
we were pleased to observe clean and quantitative conversion
to the halide exchanged product, L1-Cl in 48 hours at 40oC
(Table 1, entry 1). Importantly, in the absence of Au(I), only
traces of halide exchange product were observed, confirming
the role of Au(I) as catalyst (Table 1, entry 4). Conversion of
L1-I to L1-Br was also cleanly achieved, although the optimi-
zation process rendered improved results using slightly higher
temperatures (70oC; Table 1, entries 5-8). Subsequently, the
study was extended to the bromide containing aryl macrocycle,
L1-Br. This conversion is analogous to the well-known Cu-
catalyzed Buchwald transformation of aryl-bromides to the
corresponding aryl-iodides,44 and again it was possible to
cleanly realize the Cl and I exchanged products (Table 1, en-
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99
99
trace
95
AuCl(PPh3)
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
92
NaI (10)
4
94
18
72
72
72
72
100
100
48
100
23
30 (56)e
L1-Cl
AuCl(PPh3)
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
34
NaBr
(10)
46 (59)e
trace
42 (64)f
48
AuCl(PPh3)
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
NaI (10)
67
16
aConditions: 15.3 μmol L1-X, 10 mol% Au(I), MY, 0.5 mL CD3CN, N2; see
Au(I) catalyst structures in Scheme 2. bYields calculated using 1H NMR spectra,
1
c
with 1,3,5-trimethoxybenzene as internal standard. Quantitative yield after 30
tries 9 and 16). As can be seen in a H NMR monitoring ex-
h using 5 mol% of Au(I) cat. In parenthesis, experiments at 70 oC. In paren-
d
e
periment (Scheme 2), the reactions proceeded cleanly and
showed no presence of intermediates during the catalytic trans-
formation of L1-Br to L1-I. Halide exchange reactions starting
from L1-Cl (Table 1, entries 17 and 24) proved to be signifi-
cantly more challenging than those with L1-I and L1-Br, likely
as a result of the stronger Ar-X bond (Ar-Cl = 97.3 kcal·mol-1,
Ar-Br = 82.7 kcal·mol-1 and Ar-I = 66.9 kcal·mol-1).45 With
respect to the iodination of L1-Cl, even after prolonged reac-
tion times of up to 350 h (Table 1, entry 21) we were unable to
realize quantitative conversions. The low conversion of L1-Cl
to L1-Br using NaBr (30% yield, Table 1, entry 17) may be
also attributed to the low solubility of the initial halide salt in
acetonitrile. The use of more soluble LiBr improved the yield
of L1-Br to 56% (Table 1, entry 17). The precipitation of the
sodium salts (NaCl and NaBr) from the CD3CN solution may
be key to understanding the catalytic cycle turnover towards
heavier halide products;14 no halide exchange reaction is ob-
served in the exchange of aryl chloride towards aryl bromide or
thesis, LiBr (10 eq.) as bromide source. f In parenthesis, yield after 350 h.
In general, although the halide exchange reactions catalyzed by
[AuCl(PPh3)] were effective, in some cases they struggled to
reach completion after extended periods of time (days). To
tackle the poor reactivity of AuCl(PPh3), we hypothesized that
the availability of the coordination site on the Au(I) center
might have an important effect on the reaction outcome. Re-
cently, theoretical calculations have suggested that a putative
oxidative addition of aryl halides to Au(I) would be much eas-
ier when employing [Au(I)L]+ complexes.46 Although these
kind of cationic Au(I) complexes have proven very unstable,
the use of a weakly coordinating counterion can prevent such
decomposition. In view of this we tested the efficiency of
[Au(NTf2)PPh3] (NTf2 = bis(trifluoromethanesulfonyl)imidate)
as Au(I) catalyst in the previously described halide exchange
transformations (Scheme 3).47-48 The results obtained were
comparable to those using [AuCl(PPh3)] (see Table 1), except
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Journal of the American Chemical Society
for the iodination of L1-Br, which was accomplished in the
same excellent yields in only 8 h (Table 1, entry 14). We also
1
2
3
4
attempted the chloride abstraction from AuCl(PPh3) by silver
salts with an accompanying non-coordinating anion, such as
BF4- or SbF6- in acetonitrile solution, to occupy the vacant co-
ordination site by
a
labile solvent molecule.49-50
5
[Au(MeCN)PPh3]SbF6 was synthesized but its use as a cata-
lyst proved unsuccessful due to rapid decomposition into
[Ph3P-Au-PPh3]+ species and Au(0) in solution at temperatures
above 25 ºC.
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Scheme 3. Au(I) catalysts used in this work.
Au(I)-catalyzed C-F bond forming reactions with model
macrocyclic substrates. Since catalytic halide exchange reac-
tions mediated by Au(I) were shown to be successful with the
combination of any pair of L1-X and MY (where X, Y = Cl,
Br, I), we then sought to investigate the possibility of halide
exchange for the realization of fluorination products using
AuCl(PPh3), Au(NTf2)(PPh3) or [Au(NCMe)IPr](SbF6) as
catalysts. Initially we tested Bu4NF as fluoride source, but we
found it to be completely inefficient. In contrast, addition of
two equivalents of AgF, a typical fluoride source for catalytic
fluorination reactions,53 to a solution of ligand L1-Cl and 10
mol% of AuCl(PPh3) or Au(NTf2)PPh3 at 70ºC afforded the
desired fluorination product, L1-F (Table 2, entries 1-2), albeit
in low but encouraging 32% and 36% yields respectively.
Changing L1-Cl for L1-Br or L1-I as starting substrate provid-
ed improved yields in shorter reaction times (Table 2, entries
10 and 19), although the background reaction (blank experi-
ments, Table 2 entries 4, 9, 13, 18, 20) becomes more signifi-
cant than when using L1-Cl, which can be explained by the
previously demonstrated Ag mediated fluorination catalysis
operating with the intermediacy of an aryl-Ag(III) species.13
The permethylated macrocyclic substrates, L5-X (X= Cl, Br),
exhibited significantly enhanced fluorination yields when
compared to their L1-X analogues (Table 2, entries 5-9 and 14-
18), which suggested that the strong basicity of the F- anion
directly affected the secondary amines in the reactions using
L1-X. It is known that the secondary amines of the macrocyclic
L1-X ligand are relatively easily deprotonated upon formation
of aryl-Cu(III) and aryl-Ag(III) species,13, 54 triggering the for-
mation of side-products such as intramolecular C-N coupling
products. The presence of L1-N-intra compound13-14, 55 as a by-
product (Table 2) may suggest the formation of an organome-
tallic Au-C bond (see Mechanistic insight section for discus-
sion). In the case of L1-Cl and L5-Cl, only residual fluorina-
tion is observed if Au(I) is excluded (Table 2, entries 4 and 9),
thus demonstrating a distinctive genuine reactivity for Au ca-
talysis compared to Ag-mediated transformations. Interesting-
ly, 14% and 23% of L5-F were obtained using KF as the fluo-
ride source when fluorinating L5-Cl and L5-Br respectively
(Table 2, entries 5 and 14), suggesting that Au has a central
role in this fluorination catalysis.
1
Scheme 2. H NMR spectra of the evolution of the benzylic re-
gion during the halide exchange reaction from L1-Br to L1-I (Ta-
ble 1, entry 13) in CD3CN: (a) t = 0 h, (b) t = 2 h, (c) t = 8 h and
(d) t = 18 h. □ L1-I,  L1-Br and  1,3,5-trimethoxybenzene
(internal standard).
In view of the difficulties in isolating an alternative
triphenylphosphine-based Au complex that shows improved
reactivity, we sought another ancillary ligand. Over the past
few years, Nolan and co-workers have prepared a range of
complexes with N-heterocyclic donor ligands (NHC) replacing
the common phosphines.49-, 51-52 This type of ligand has been
reported to stabilize cationic Au(I) much more efficiently than
PPh3, whilst maintaining its catalytic properties. Hence, we
prepared
[Au(NCMe)IPr]SbF6
(IPr
=
1,3-bis(di-
isopropylphenyl)imidazol-2-ylidene) starting from commer-
cially available AuCl(IPr) (Scheme 3). Subsequently we tested
its catalytic efficacy towards halide exchange reactions within
the aryl halide macrocyclic substrates (Table 1). To our de-
light, good to excellent yields were also attained employing
significantly shorter reaction times, especially for the chlorina-
tion of L1-I and L1-Br (Table 1, entries 3 and 11) and the io-
dination of L1-Br and L1-Cl (Table 1, entries 15 and 23). For
comparison, in some reactions AuCl(IPr) or AuBr(IPr) were
used instead of [Au(NCMe)IPr](SbF6) and the same results
were obtained (see Table S3). This is an important indication
that the catalytic activity of a Au(I) complex, namely
[AuX(L)], is predominantly governed by the nature of the an-
cillary ligand L rather than the counteranion X.
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electron-withdrawing groups (eg. p-nitrophenol = 35%, Table
Table 2. Catalytic fluorination reactions with L1-X and L5-X in
CD3CN under N2.a
1
2
3
4
5
6
7
8
3, entry 6). Finally, we found that the nature of the Au(I) cata-
lyst has a clear impact in the yields and temperature where
reactions can be conducted. When [Au(NCMe)IPr](SbF6) was
used as catalyst, coupling with p-chlorophenol can be achieved
in moderate yields at room temperature, conditions where the
background reaction is absent (Table 3, entries 9-10). When
using thiophenol we were unable to detect any C-S coupling
product (Table 3, entry 11), probably due to the affinity of thi-
ols to coordinate to Au(I), thus blocking the catalyst. It is also
interesting to highlight the presence of a small amount of L1-H
byproduct in some of the C-O catalysis in Table 3, which
again suggests the intermediacy of an aryl-Au bond.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield
MF
T
(oC)
Entry
Ln-X
Au(I) (10 mol%)
t (h)
Ln-F
(%)b
32c
36c
64d
6
(eq.)
1
2
L1-Cl
AgF (2)
AgF (2)
AgF (2)
AgF (2)
KF (5)
AuCl(PPh3)
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
[Au(NCMe)IPr]+
AuCl(PPh3)
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
70
70
70
70
70
70
70
70
70
40
40
40
40
70
40
40
40
40
40
40
72
72
24
72
72
72
72
12
72
48
48
48
48
48
48
48
6
Table 3. Catalytic fluorination reactions with L1-Br and L5-Br
in CD3CN under N2.a
3
4
5
L5-Cl
14e
6
AgF (2)
AgF (2)
AgF (2)
AgF (2)
AgF (2)
AgF (2)
AgF (2)
AgF (2)
KF (5)
51
7
50
8
98
9
4
10
11
12
13
14
15
16
17
18
19
20
L1-Br
L5-Br
AuCl(PPh3)
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
[Au(NCMe)IPr]+
AuCl(PPh3)
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
49f
54g
68h
42
23e
100
100
100
100
56i
54
Yield L1-XPh(R) (%)b
Entry
X
O
R
Au(I) (10 mol%)
25 ºC
40ºC
-
70 ºC
34c
1
2
H
H
AuCl(PPh3)
Au(NTf2)PPh3
Au(NTf2)PPh3
Au(NTf2)PPh3
[Au(NCMe)IPr]+
Au(NTf2)PPh3
Au(NTf2)PPh3
Au(NTf2)PPh3
[Au(NCMe)IPr]+
-
-
-
51
41
45d
44f
15
32
52
61
15
0
75
3
Me
OMe
OMe
NO2
CF3
Cl
-
71
89e
87g
AgF (2)
AgF (2)
AgF (2)
AgF (2)
AgF (2)
AgF (2)
4
-
5
-
6
-
35
48
24
24
7
-
56
L1-I
AuCl(PPh3)
-
8
29
42
<1
-
79 (61)h
84 (83)h
45
9
Cl
aConditions: 15.3 μmol L1-X or L5-X, 10 mol% Au(I), MF, 0.5 mL CD3CN,
10
11
Cl
b
1
N2. Yields calculated using H NMR spectra, with 1,3,5-trimethoxybenzene as
internal standard. c 6% of L1-N-intra observed. 5% of L1-N-intra observed.
d
e
S
H
Au(NTf2)PPh3
0
0% yield when Au(I) source is absent. f 7% of L1-N-intra observed. g 9% of L1-
N-intra observed. h 8% of L1-N-intra observed. i 5% of L1-N-intra observed.
aConditions: 15.3 μmol L1-Br or L5-Br, 10 mol% Au(I), nucleophile, 0.5 mL
CD3CN, N2, 24h. bYields calculated using 1H NMR spectra, with 1,3,5-
trimethoxybenzene as internal standard. c 10% L1-Cl observed in addition to C-
f
O coupling product. d 2% of L1-H observed. e 9% of L1-H observed. 4% of L1-
H observed. g 10% of L1-H observed. h yield after 8 h in parenthesis.
Au(I)-catalyzed C-O bond forming reactions using phenols
with model macrocyclic substrates. To the best of our
knowledge there are no reported examples of Au-catalyzed
Ullmann-type coupling reactions and therefore, to further ex-
pand the substrate scope and applicability of the catalyst sys-
tem, we decided to investigate the potential for C-O and C-S
bond formation using a range of substituted phenols and
thiophenol. We were pleased to observe that with the phenolic
substrates it was possible to form the desired coupling prod-
ucts (Table 3, entries 2-8). It was found to be necessary to use
Au(NTf2)PPh3 as Au(I) source for this study as during experi-
ments using AuCl(PPh3) we observed rapid formation of the
Cl-exchanged product. The amount of L1-Cl formed did not
exceed 10% yield, confirming that the chloride source was the
Au(I) salt, and thus strongly suggesting that C-Br bond activa-
tion mediated by Au had occurred (Table 3, entry 1, and Figure
S17 in Supporting Information). On the other hand, it can be
seen that variation of the electronic properties of the phenol has
an important effect on the yield, with electron-donating sub-
stituents typically giving higher yields (eg. p-methoxylphenol
= 89%, Table 3, entry 4) compared with phenols with strongly
Au(I)-catalyzed Halide exchange and C-O bond forming
reactions with non-macrocyclic substrates. Following these
successful studies we attempted to transfer the reactivity from
the aryl halide macrocyclic model substrates to other com-
pounds in order to gain further insight into the mechanism and
also demonstrate further reactivity (Scheme 4). Since the
strongly coordinating ligands PPh3 and IPr required to achieve
the catalysis shown above are likely to remain coordinated to
the Au center throughout the course of the reaction, we won-
dered if the macrocyclic triamine chain was necessary for the
reaction to proceed. Therefore, we explored the representative
catalytic performance of halide exchange and C-O coupling
with three different aryl halide substrates containing a single
chelation site (N atom) and one without (2a-d, Scheme 4).
Among the different Au(I) sources used previously, the cation-
ic [Au(NCMe)IPr]SbF6 complex was selected for this study as
it allowed vastly improved results. Attempts towards bromide
to iodide exchange with 2-bromo-1,3-dimethylbenzene (3a)
afforded no product, suggesting that Au is not catalyzing the
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halide exchange reactions through its Lewis acid character and
The C-O coupling reactions were also investigated with the
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8
that a chelating group is crucial for catalysis to occur. Subse-
quently, aliphatic amine chelating groups (both secondary and
tertiary amines in analogy to the aryl halide macrocycles L1-Br
and L5-Br respectively) were introduced and again little or no
halide exchange was observed when acetonitrile was employed
as solvent (Scheme 4, 3b and 3c). Upon replacement of the
aliphatic amine moieties with a pyridyl chelating group, we
were pleased to observe 46% of the halide exchanged product
(Scheme 4, 3d). Importantly, 0% conversion was obtained in
the absence of Au. The pyridyl chelating groups are signifi-
cantly different in terms of their electronic properties to amine
chelating groups. However, we propose that the higher activity
observed with the pyridyl group is a consequence of the in-
creased rigidity of the resulting chelate enabling the required
disposition of the Au(I) reactive intermediate to activate the C-
X bond of the substrate. These results demonstrate the im-
portance of rigid chelation and highlight the beneficial nature
of the rigid aryl halide macrocycle used in this study. Chang-
ing the solvent to DMSO provided increased yields of the hal-
ide exchanged products except in the case of the non-chelate
containing substrate, 3a, (Scheme 4a), thus following a similar
trend as in acetonitrile.
non-macrocyclic substrates and the same trend as for the hal-
ide exchange reaction was obtained. The more rigid 2-(2-
bromophenyl)pyridine (2d) afford quantitative yields for the
biaryl ether 4d, whereas minor or no conversion was achieved
when using substrates 2a-c (Scheme 4b). It is worth noting
that the reaction requires the presence of a base to achieve
initial deprotonation of the phenol-derivative. Nevertheless, the
use of the corresponding independently prepared sodium p-
chlorophenolate proved more beneficial to the reaction out-
come (Scheme 4b).
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Scheme 5. Substrate scope of the Au(I)-catalyzed C-Heteroatom
bond forming reactions (conversions in parenthesis).
Table 4. % yields obtained during the initial stages of the pCl-
phenolate coupling to 2d and its p-substituted derivatives.
Yield (%)
t (h)
R = H (4d)
R = CF3 (4da)
R = OCH3 (4db)
1
2
4
35
61
78
41
73
93
>99
>99
>99
Thereafter we explored the substrate scope to evaluate the po-
tential of these transformations and to gain mechanistic in-
sight. We expanded the scope of the non-macrocyclic sub-
strates, preparing 2da and 2db, which contain an electron-
withdrawing group (pCF3, 2da) or an electron-donating group
(pOMe, 2db) in the para-position with respect to the bromine
atom. Both substrates were tested in the Au(I)-catalyzed io-
dination of aryl bromides as well as the C-O bond formation to
form the biaryl ether using pCl-phenolate as nucleophile
(Scheme 5a). The halide exchange reactions afforded similar
yields of the iodinated product 3da and 3db under the same
experimental conditions as when using 2d, and also excellent
outcomes where found for the formation of the corresponding
biaryl ether products 4da and 4db. Kinetic studies at the early
stages of the C-O coupling reactions reveal higher yields for
the p-trifluoromethyl substituted substrate (4da), although no
unambigous mechanistic information can be ascertained from
Scheme 4. Screening of ortho-chelating groups (yields for blank
experiments without Au catalyst in parenthesis) for (a) bromide
to iodide exchange (yields calculated by GC analysis) and (b) C-
O coupling with sodium p-chlorophenolate (yields calculated by
**
1H-NMR).* X = Br, 65% yield after 24h at 90ºC; X = I, yield
at 90ºC.
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the values obtained (Table 4). In addition, in order to explore were observed at expense of the formation of side-products,
1
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3
4
5
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7
8
the utility of this methodology towards the synthesis of other
products, 2d was reacted with sodium methoxide as nucleo-
phile, providing the aryl methyl ether 5d again in quantitative
yields (Scheme 5b). These results suggest that other substrates,
nucleophiles and reaction conditions might be found for a
more general and applicable oxidant-free Au-catalyzed reac-
tion that leads to the formation of new products of interest.
but the previously observed halide exchange reactions and C-O
couplings remained as the main transformations occurring in
the solution. Notably, H-NMR analysis of the reaction crude
at the end the catalysis indicates that the entire catalyst re-
mains in solution in the form of [Au(Br)IPr], since authentic
samples of free IPr and IPr·HOTf do not match the observed
NHC signals, whereas an authentic sample of [Au(Br)IPr]
does (Figure S35).
1
Mechanistic insights. The results obtained permit some in-
sights into the reaction mechanism although we have not been
At present we cannot fully discard any mechanism, but as
mentioned a Au(I) -interaction with the aromatic ring is un-
likely because only substrates with chelating groups give posi-
tive results. In fact, HRMS monitoring shows that [Au(OPh-
pCl)IPr] remains unaltered for 24 h under the catalytic condi-
tions used for the reaction of 2a with p-chlorophenol, with no
conversion (Figure S31). Bourissou and co-workers have pre-
viously demonstrated that an oxidative addition step is signifi-
cantly enhanced if non-linearity is forced upon Au(I).58 Given
that one chelating group in the substrate is necessary (see
Scheme 4), we hypothesize that this coordination may help in
distorting the linearity of the Au(I) resting state, and allows for
the reaction to occur upon heating (in the examples described
here temperatures of 110ºC need to be applied to overcome the
energy barrier). The observation of L1-N-intra and L1-H in C-
F and C-O coupling catalysis, is reminiscent of Cu(I)/Cu(III)
and Ag(I)/Ag(III) catalysis when using the macrocyclic model
9
able to detect a putative aryl-Au(III) species analogous to the
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13, 15
previously reported aryl-Cu(III) and aryl-Ag(III).8,
The
difficulty in isolating this key intermediate is likely related to
the challenge in avoiding Au(I) disproportionation when weak
ligands are used to stabilize Au(I), i.e. AuCl(SMe2) or bare
AuI. The use of more stabilizing PPh3 or IPr ligands enhance
catalytic turnover but do not allow the detection of a putative
square-planar aryl-Au(III), since PPh3 or IPr ligands are likely
not detached from Au(I) center during the catalytic cycle. The
latter is in agreement with the fact that one chelating group is
sufficient to translate the catalytic performance from the
macrocyclic substrate to the more simple substrates (Scheme
4). The coordination of the [Au(NCMe)IPr]SbF6 to L1-Br or
1
2d can be observed experimentally by means of H-NMR and
ESI-MS (see Supporting information, Figures S28 and S29)
1
However, a H-NMR monitoring experiment of the C-O cou-
pling catalysis of p-chlorophenol and 2d shows that under
catalytic conditions, i.e in the presence of excess of phenolate,
[Au(OPh-pCl)IPr] forms at room temperature as a catalytic
intermediate (see Figure S29 and S32). The reaction only takes
place upon heating, and once the catalysis has started, the
bromide anion released from 2d in the first catalytic cycle is
immediately trapped by Au, forming [Au(Br)IPr] (see Figure
S30). With the aim of evaluating if those species are indeed
off-cycle intermediates of the reaction, independently prepared
[Au(OPh-pCl)IPr] and [Au(Br)IPr] were tested as catalysts in
both the halide exchange and C-O bond forming reactions with
the macrocyclic and non-macrocyclic substrates, obtaining the
same results as with [Au(NCMe)IPr]SbF6 (see Table S3),
which clearly supports their intermediacy in the reaction
substrates, also pointing towards the existence of
Au(I)/Au(III) catalytic cycle.
a
We also embarked on a DFT study to gain insight into the
mechanism, and specifically we focused on the coupling of
pCl-PhO- with 3d as the model reaction, using
[Au(NCMe)IPr]+ as the catalyst (See Supporting Information
for computational details). First of all, we calculated the ther-
modynamic values of the replacement of a acetonitrile mole-
cule in [Au(NCMe)IPr]+ by the pCl-PhO- group to form
[Au(OPh-pCl)Pr], finding that this is clearly an exergonic pro-
cess (ΔG = -11.4 kcal·mol-1). The free energy balances for the
exchange of the coordinated pCl-PhO- (ΔG = 2.5 kcal·mol-1) or
iodide (ΔG = -1.4 kcal·mol-1) by 3d allows the formation of
[Au(3d)IPr]+, and suggests that the generation of the analo-
gous [Au(2d)IPr]+ may be feasible under reaction conditions,
thus in agreement with the HRMS experiments. Moreover, a
complete reaction pathway for the C-halogen functionalization
has been successfully computed at M06L level (Scheme 6),
showing a transition state for the oxidative addition step
(TSox) at 30.6 kcal/mol, and a TSred for the reductive elimina-
tion at 31.3 kcal/mol. Given the fact that reactions are con-
ducted above 90ºC, these barriers are below the kinetic limit,
thus in agreement with the experiments performed and the
rather slow reactions. DFT calculations indicate that the reduc-
tive elimination step is rate limiting, however, the fact that
both TS are very close in energy suggests that subtle changes
may favor switching to a rate limiting oxidative addition. The
energetic similarity between both TS could justify the some-
what ambiguous trend among the electronically different p-
substituted 2-(2-bromophenyl)pyridine substrates (Table 4).
We have also determined the oxidative addition/reductive
elimination Gibbs energy profile for another Au(I) isomer
where the gold cation is coordinated to 3d instead of pCl-PhO-.
However, the optimized oxidative addition TS (see Figure S37)
is about 7 kcal/mol higher in energy than TSox and TSred
described in Scheme 6.
1
mechanism. H-NMR monitoring experiments do not prove
that any of these Au species coordinate to the substrate, but the
observation of reactivity in 2b-d but not 2a suggests that this
is a requirement (see Figure S31). Indeed, under HRMS condi-
tions we can detect the in situ formation of [Au(2d)IPr]+ by
substitution of the coordinated phenolate or the bromide (Fig-
ures S33-S34), thus providing experimental support to our
proposal. Also, species [Au(3d)IPr]+ and [Au(4d)IPr]+ are
observed in the final crude reaction mixtures (Figures S10 and
S30).
The possibility that Au(0) colloids could be the active species
responsible for this chemistry was also considered. In order to
assess whether the catalyst is homogeneous or heterogeneous,
we ran reactions under identical conditions except for the pres-
ence of a large excess of mercury (ca. ~500 eq with respect to
Au catalyst, under heavy stirring), which acts as a poison to-
wards nanoparticles.56-57 A quenching of reactivity would
strongly suggest colloidal catalysis. However, when perform-
ing halide exchange catalysis and C-O coupling using both the
aryl-Br macrocylic model substrate (L1-Br) and the bromoaryl-
pyridine (2d), we did not detect a significant decrease in activi-
ties (see Table S2). Somewhat lower yields (10-30% lower)
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Scheme 6. DFT reaction profile for the oxidative addition / reductive elimination steps of [Au(OPh-pCl)] over 3d substrate. Relative
Gibbs energy values in acetonitrile solution are given in kcal·mol-1 and selected bond distances in Å (H atoms are omitted for clar-
ity).
nucleophilic displacement of the o-methoxy group in compara-
ble substrates to 2d by organolithium and Grignard reagents.
This suggests that our reported reaction indeed proceeds
Nucleophilic aromatic substitution was also explored computa-
tionally, where the cationic Au(I) would act as a Lewis acid to
increase the reactivity of the aryl-I moiety. Remarkably, all the
TS searches for the direct attack of the phenolate to 3d actually
through a mechanism different to a Au-assisted nucleophilic
aromatic substitution.59
converged to TSox (Scheme 6), thus driving the reaction
through a Au(III) species and rendering the possibility of a
direct nucleophilic attack on the aryl-carbon of 3d unlikely.
A preliminary proposal for the Au(I) catalyzed C-O cross cou-
pling based on the experimental and DFT study findings pro-
vided above is depicted in Scheme 7, involving the formation
of the C-O product 4d via the intermediacy of [Au(OPh-
pCl)IPr]and [Au(Br)IPr] resting state forms of the catalyst.
This alternative mechanism was also studied experimentally.
Having in hand the isolated methoxide insertion product 5d,
we studied the cationic Au(I)-mediated displacement of the
methoxy group in the presence of sodium pCl-phenolate as
nucleophile under the same reactions conditions described for
2d. After sufficient time to allow any reaction to proceed we
quantitatively recovered the starting material. This is in con-
trast to a related nucleophilic aromatic substitution reported by
Meyers and co-workers in the late 1970’s describing a
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Catalunya (2009SGR637). F. A.-P. thanks Universitat de Girona
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2
3
4
for a predoctoral grant. M.F and J.L.-F. thank a PhD grant and a
RyC contract from Spanish MINECO, respectively. X.R. also
thanks ICREA-Acadèmia award. J.S. thanks UdG for a PhD
grant. J. S. also wants to thank his father for everything he has
done.
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