Au-Catalyzed Biaryl Coupling to Generate 5- To 9-Membered Rings: Turnover-Limiting Reductive Elimination versus ?-Complexation

Article abstract of DOI:10.1021/jacs.6b10018

The intramolecular gold-catalyzed arylation of arenes by aryl-trimethylsilanes has been investigated from both mechanistic and preparative aspects. The reaction generates 5- to 9-membered rings, and of the 44 examples studied, 10 include a heteroatom (N, O). Tethering of the arene to the arylsilane provides not only a tool to probe the impact of the conformational flexibility of Ar-Au-Ar intermediates, via systematic modulation of the length of aryl-aryl linkage, but also the ability to arylate neutral and electron-poor arenes - substrates that do not react at all in the intermolecular process. Rendering the arylation intramolecular also results in phenomenologically simpler reaction kinetics, and overall these features have facilitated a detailed study of linear free energy relationships, kinetic isotope effects, and the first quantitative experimental data on the effects of aryl electron demand and conformational freedom on the rate of reductive elimination from diaryl-gold(III) species. The turnover-limiting step for the formation of a series of fluorene derivatives is sensitive to the reactivity of the arene and changes from reductive elimination to ?-complexation for arenes bearing strongly electron-withdrawing substituents (σ > 0.43). Reductive elimination is accelerated by electron-donating substituents (ρ = -2.0) on one or both rings, with the individual σ-values being additive in nature. Longer and more flexible tethers between the two aryl rings result in faster reductive elimination from Ar-Au(X)-Ar and lead to the ?-complexation of the arene by Ar-AuX2 becoming the turnover-limiting step.

Full text of DOI:10.1021/jacs.6b10018

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Article
Au-catalyzed Biaryl Coupling to Generate 5- to 9-membered Rings:
Turnover-Limiting Reductive Elimination versus #-complexation
Tom J. A. Corrie, Liam T Ball, Christopher A. Russell, and Guy C. Lloyd-Jones
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 12 Dec 2016
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Au-catalyzed Biaryl Coupling to Generate 5- to 9-membered Rings:
Turnover-Limiting Reductive Elimination versus π-complexation
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Tom J. A. Corrie,† Liam T. Ball,†,§ Christopher A. Russell,§ and Guy C. Lloyd-Jones*,†
†University of Edinburgh, EaStChem, Joseph Black Building, David Brewster Road, Edinburgh, EH9 3FJ, U.K.
§School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
ABSTRACT: The intramolecular gold–catalyzed arylation of arenes by aryltrimethylsilanes has been investigated from both
a mechanistic and preparative aspect. The reaction generates five to nine membered rings, and of the 44 examples studied,
ten include a heteroatom (N, O). The tethering of the arene to the arylsilane not only provides a tool to probe the impact of
the conformational flexibility of Ar–Au–Ar intermediates, via systematic modulation of the length of aryl-aryl linkage, but
also the ability to arylate neutral and electron-poor arenes - substrates that do not react at all in the intermolecular process.
Rendering the arylation intramolecular also results in phenomenologically simpler reaction kinetics, and overall these fea-
tures have facilitated a detailed study of linear free energy relationships, kinetic isotope effects, and the first quantitative
experimental data on the effects of aryl electron-demand and conformational freedom on the rate of reductive elimination
from diaryl gold(III) species. The turnover-limiting step for the formation of a series of fluorene derivatives is sensitive to
the reactivity of the arene and changes from reductive elimination to π-complexation for arenes bearing strongly electron-
withdrawing substituents (σ >0.43). Reductive elimination is accelerated by electron-donating substituents (ρ= ̶ 2.0) on one
or both rings, with the individual σ-values being additive in nature. Longer and more flexible tethers between the two aryl
rings results in faster reductive elimination from Ar-Au(X)-Ar, and to the π-complexation of the arene by Ar-AuX2 becoming
the turnover-limiting step.
oxidant modification allows arylation of a range of heterocy-
cles.8
Introduction
Transition metal-catalyzed cross-coupling has revolutionized
synthesis,1 with the biaryl motif a major focal point for research
in this area.2 The union of aryl-(pseudo)halides and aryl-metallic
reagents have been extensively studied, and there is now sub-
stantial interest in more step- and atom-economic variants. In
this regard, the reaction of arenes with aryl-metallic reagents,
one class of the so-called 'direct arylation' reaction, has received
significant attention.3 Catalysis by gold is emerging as a power-
ful synthetic tool.4 We recently reported a gold-catalyzed inter-
molecular arylation of electron-rich arenes by aryltrimethylsilanes
(Scheme 1).5
Major advances have also been made towards understanding
the unique reactivity and selectivity of catalytic reactions pro-
ceeding via Au(I) and Au(III) intermediates.6,9 Nonetheless, in
comparison to many transition metal catalyzed processes,
mechanistic understanding of homogeneous gold catalysis re-
mains less well developed. In 2014 we reported our initial
mechanistic investigations into the gold-catalyzed intermolecular
arylation (Scheme 1).9h Study of the pre-catalyst activation pro-
cess revealed that during an approximately 2 hour-long induc-
tion period, the Au(I)-phosphine complex was oxidized to yield
PPh3O and the active gold catalyst: a solvated AuX3 species (X =
CSA, OTs). By changing to a thtAuBr3 pre-catalyst (tht = tetra-
hydrothiophene) we were able to reduce the induction period
to around 300 seconds; again liberating a solvated 'ligand-free'
AuX3 species. Using this pre-catalyst system and a specifically
tailored substrate (arylthiophene 1, Scheme 2, upper) the reac-
tion kinetics were sufficiently tractable to allow us to determine
the empirical rate law by 19F NMR, and to deduce that intermo-
lecular Au(III)-arene π-complexation is the turnover-limiting
step.9h However, our conclusions were predominantly based on
detailed study of this single well-behaved model system. Infor-
mation on some of the other steps in the cycle was less clear,
being gained indirectly from competition experiments, litera-
ture precedent, and model stoichiometric reactions.
PPh3AuOTs (1-2 mol%)
PhI(OAc)2 (1.3 equiv.)
CSA (1.5 equiv)
SiMe3
ZH
ZH
ZSi
+
ZSi
CHCl3/MeOH (50:1)
rt
ZSi = EDG, H, EWG
ZH = EDG
Scheme 1. Au-catalyzed intermolecular arene-arylsilane oxida-
tive coupling, as initially reported (2012).5 CSA = camphorsul-
fonic acid. For further advances, see references 6-8.
The process is operationally simple, proceeds under air, often
at room temperature, at low catalyst loadings (1-2 mol%), and
with broad functional-group tolerance. In subsequent develop-
ments, Itami and Sagewa demonstrated that pyridylidene Au-
complexation facilitates arylation of isoxazoles, indoles and
benzothiophenes,6 Jeon applied Au-catalyzed arylation to func-
tionalize ortho-silyl aryl triflates generated via Rh/Ir-catalyzed
traceless ortho-CH silation,7 and we reported that silane and
Gaining mechanistic insight to other steps in the cycle has
become an important goal. However, to date the process has
been limited to π-rich arenes and some heterocycles. Neutral or
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Page 2 of 11
electron-poor arenes act solely as spectators to the competing (Tables 1 and 2) were cyclized, affording 5- to 9-membered rings
1
2
3
4
5
6
7
8
homocoupling of the aryl trimethylsilane. This substantially
limits the range of arenes that can be explored in, for example,
linear free-energy relationships, even by way of analysis of rela-
tive rather than absolute rates.
in good to excellent isolated yields.
O
R = H, Me
OR
'HCIB' 2
O
O
Me
S
AcO
I
OAc
F3CCO2
I
O2CCF3
O
I
Me
CSA
3
'PIFA'
Ar
Previous work
thtAuBr3 (1-2 mol%)
PhI(OAc)2 (1, 1.3 equiv.)
Ar
Br
SiMe3
+
CSA (1.5 equiv)
S
The structures of the largest rings (5ah, 5ai, Table2, entries
17,18) were confirmed by single crystal X-ray diffraction. Alt-
hough a number of other intramolecular direct arylation strate-
gies have been reported,10 the gold-catalyzed cyclization displays
excellent functional group tolerance, proceeds at low reaction
temperatures, uses readily prepared TMS-bearing starting mate-
rials, and yields 5-9 membered ring products bearing a diverse
range of substituents, from m-CF3 to p-OMe. For the majority of
examples, 1-2 mol% Au allowed complete conversion, at 27°C
in a reasonable timescale; with some substrates substantially
lower loadings were possible. For example cyclization of 4n
(Table 2, entry 3) was complete in under 10 minutes using 1
mol% Au (95% yield) and at 0.06 mol% Au still afforded dime-
thylfluorene 5n in 80% yield, with formal turnover number of
1330. In contrast, the cyclization of 4ah (Table 2, entry 17) to
generate 8-membered 5ah required 4 mol% Au, and 9-
membered 5ai (Table 2, entry 18), required heating to 50 °C
(52% yield). Although the formation of 8- and 9- membered
rings via metal catalyzed direct arylation has been reported,11
examples involving simple aryl rings (no directing groups) are
rare.
CHCl3/MeOH (50:1)
rt
9
H
Br
S
F
F
Ar = p-C6H4F
Br
1
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Ar
π−arene
X
X
L
complexation
III
X
S
Au
III
Au
1
F
L
F
ZH,Si = EDG, H, EWG
This work
Me3Si
H
tether
Au(I/III)
redox
L
X
X
ArI
III
Au
ZSi
ZH
X
ArIX2
L = MeOH, arene,
or vacant site
C-Si Auration
ZH
I
L
Au
X
X
tht-oxide
X
III
ArX2
thtAuBr3
Au
ZH
L
ZSi
Reductive
pre-catalyst
Elimination
π−arene
Complexation
tether
ZH
ZSi
ZH
L
III
H
Au
X
X
L
III
Au
In some cases, in particular anisyl and naphthyl substrates 4a,
4i and 4s, oxidant (HCIB, 2)12 reacts directly with electron-rich
C-H Auration
ZSi
X
ZSi
arene to generate
a diaryliodonium salt via an SEAr
mechanism.13 This competing process, which is not Au-
catalyzed, severely reduced the yield with certain examples.
Changing from HCIB (2) to PIFA (3) largely eliminated diaryli-
odonium formation, allowing 5a, 5i and 5s to be obtained in
80-88% yields. The impact of oxidant is exemplified in the cy-
clization of 4a, Table 1.
Scheme 2. Mechanistic studies of Au-catalyzed arene-arylsilane
oxidative coupling. tht = tetrahydrothiophene. CSA = cam-
phorsulfonic acid. L, X = unspecified neutral and anionic lig-
ands. The intermolecular process9h is limited to π-rich arenes.
Herein we report on the intramolecular process (Scheme 2,
lower). Conducting the arylation intramolecularly induces a
number of useful changes to the system: i) in contrast to the
intermolecular reaction, the reactions proceed with very repro-
ducible and, in the main, phenomenologically-simple kinetics,
vide infra; ii) a very broad range of arenes, including highly elec-
tron-deficient examples, can be arylated without competing
arylsilane homocoupling; and iii), the tether between the arene
and the aryl silane can be used to systematically perturb arene-
Au conformational flexibility, and to modulate the effective
molarity of arene, in the catalytic intermediates. Overall the
intramolecular system allows substitution patterns (ZSi and ZH)
and tether lengths to be tuned to provide the reactivity and
kinetic regulation requisite for elucidation of mechanistic fea-
tures that are not accessible in the intermolecular version. Using this
platform we have gained insight into arene auration, Wheland
intermediate generation and, uniquely, reductive elimination.
Table 1. Effect of oxidant (2, 3) on the cyclization of 4a.
SiMe3
thtAuBr3
oxidant (2 or 3)
CHCl3/MeOH (50:1)
OMe
5a
4a
OMe
rt
Conversion of 4a to 5a
HCIB (2)a
thtAuBr3
PIFA (3)b
85%
0.25 mol%
0.5 mol%
1 mol%
11%
17%
33%
42%
90%
88%
2 mol%
90%
a
generated in situ from PhI(OAc)2 (1.1 equiv) + CSA (1.3 equiv). bPIFA
(3, 1.1 equiv). Conversion by 1H NMR using internal standard (CH2Br2).
MOMO
OMOM
OMe
Conditions
OMe
Results and Discussion
X
OMe
MeO
OMe
OMe
6a/b
7
Preparative Arylation We began by exploring preparative
cyclization, using 'HCIB' (2) or 'PIFA', (3) as the oxidant, and
the rapidly-activating pre-catalyst thtAuBr3 (vide supra)9h in
CHCl3/MeOH at 27 °C. A series of 35 aryl-TMS substrates
6a: X = SiMe3: thtAuBr3 (5 mol%), 3 (1.2 equiv), CHCl3/MeOH (50:1), 2.5 h, 27 °C, 75%
6b: X = Cl: Pd(OAc)2 (10 mol%), K2CO3 (2 equiv), DMA, 14 h, 145 °C, 69%11f
Scheme 3. Au / Pd catalyzed direct arylation of 6a / 6b.
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Suppression of the background diaryliodonium formation us- plex mixture, due to diaryliodonium salt generation and acid-
1
2
3
4
ing PIFA (3) allows substantially lower catalyst loadings to be
employed.14 The beneficial effect of replacing HCIB (2) with
PIFA (3) was further explored by conversion of 6a (X = TMS) to
7, Scheme 3, requiring arylation of a highly electron-rich tri-
methoxy benzene ring.15 Thus, whilst HCIB (2) led to a com-
mediated in situ MOM deprotection, use of PIFA (3) afforded
the 7-membered ring allocolchinoid skeleton15 7 in 75% yield,
with the MOM group intact. An analogous Pd-catalyzed process
using 6b (X = Cl) requires substantially more forcing conditions
(145 °C).11f
5
6
7
8
9
Table 2. Preparative gold-catalyzed cyclizations (35 examples) of 4a-4ai to 5a-5ai at 27 °C.a
Entry
Substrate
Product
(Yield, Time)
Entry
Substrate
Product
(Yield, Time)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
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(88%, 2 h)b
(94%, 1 h)
(81%, 1 h)
(90%, 4 h)
R = OMe
5a
SiMe3
5x
5y
SiMe3
(72%, 1 h)
(91%, 1 h)c
H
5b
5c
5d
5e
5f
R = H
10
1
t-Bu
Cl
R
Cl
c 5z
(82%, 16 h)
CF3
5x-z
R
R
4a-g
OPiv (81%, 6 h)
R
4x-z
5a-g
R
(80%, 15 h)
(92%, 16 h)c
CF3
OTf
5g
R
O
(95%, 1 h)d
(80%, 1 h)b,d
SiMe3
R = Me
OMe
5h
5i
SiMe3
2
3
4
5
11
12
5aa
R = H
t-Bu
(86%, 2 h)c,f
R
O
F
(60%, 1 h)c,f 5ab
(85%, 2 h)d 5j
(90%, 3 h)d
(88%, 16 h)d,e
(78%, 15 h)d
5aa-ab
5h-m
Cl
5k
R
4h-m
4aa-ab
CF3
OTf
5l
5m
SiMe3
Me
Me
Me
O
(95%, 10 min)
5n
SiMe3
R = H
F
R
(86%, 1 h)e,c,f
(89%, 15 min) 5o
(91%, 1 h)c
5p
Me
O
4n-p
Cl
R
Me
5ac
Me
5n-p
4ac
SiMe3
F
13
14
SiMe3
(85%, 15 h)c
(87%, 16 h)
F
4q
5q
5ad
4ad
SiMe3
Ms
N
F
SiMe3
F
(89%, 5 h)
N
Me
Ms
4r
5r
Me
(73%, 16 h)c
4ae
5ae
SiMe3
15
16
6
7
8
SiMe3
O
(80%, 1 h)b
O
4s
(76%, 16 h)c,e
5s
4af
5af
SiMe3
O
SiMe3
Me
Me
(76%, 1 h)
O
(82%, 15 h)c
Me
Me
Me
4t
F
5t
Me
Me
4ag
5ag
F
Me
Me3Si
Me
17
18
O
SiMe3
(75%, 14 h)g
(79%, 1 h)b,c,d
Me
O
4u
5u
4ah
5ah
SiMe3
O
9
SiMe3
O
(52%, 16h)e,g,h
O
R = H (87%, 30 min)
5v
(94%, 1 h)
O
R = CH2NPhth
5w
R
4ai
R
4v-w
5v-w
5ai
aUnless otherwise stated: 4 (0.50 mmol), thtAuBr3 (1 mol%), PhI(OAc)2 (0.55 mmol), CSA (0.65 mmol) in CHCl3/MeOH (50:1, 0.1
M).bPhI(OCOCF3)2 3, (0.55 mmol) replaces 1/CSA. cthtAuBr3 (2 mol%). dRatio of 2-/4-regioisomers: 5h (95:5), 5i (88:12),5j (97:3), 5u (97:3)
and 3-/1-regioisomers: 5ac (89:11). eCSA (1.0 mmol).f 0.05 M 4.gthtAuBr3 (4 mol%). h50 °C. Phth = phthalimido. Piv= t-BuCO2.
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Mechanistic Study The intramolecular arylation, particularly The pseudo-zero order kinetics preclude an intermolecular
the examples generating substituted fluorene products16 (entries
1-8, Table 2), proved ideal for mechanistic study. Firstly, as not-
ed above, the intramolecular process tolerates a very much larg-
er range of arene substituents than the intermolecular version,
where only electron rich arenes are tolerated. This key feature
has allowed detailed analysis of linear free energy relationships -
both for the silane and the arene. Secondly, the reactions tend
to proceed with reproducible and (phenomenologically) simple
kinetics, often pseudo zero-order vide infra, without significant
side-product formation. In contrast, the intermolecular system
display complex kinetic profiles and often suffers from compet-
ing aryl silane homocoupling. Thirdly, deuterium labels can be
readily installed at strategic positions to analyze for KIEs at key
steps. And finally, the tether length between the arenes is readi-
ly varied, allowing the kinetics of intramolecular arene capture
to be modulated. Overall, in combination with earlier data,9h
the system allows a more holistic analysis of the catalytic cycle.
turnover limiting step, or an intermolecular pre-equilibrium,
and thus cannot involve Au(I/III) redox by PhIX2, or C-Si au-
ration (Scheme 2). In a general sense, this confines the turno-
ver-rate limiting step to being one of: intramolecular π-
complexation, C-H auration, reductive elimination, ligand dis-
sociation, or intra-complex reorganization / isomerization.
1
2
3
4
5
6
7
8
Eyring analysis, between 7 and 37 °C, afforded ΔS‡ = +21 e.u
(Figure 1, lower); opposite in sign to the intermolecular aryla-
9
tion (Scheme
2 upper) where turnover-rate limiting π-
10
11
12
13
14
15
16
17
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complexation induces a strongly negative ΔS‡.9h Although inter-
pretation of activation parameters must be taken with care, the
results suggest that the turnover-rate limiting step for the intra-
molecular system occurs after π-complexation, which would be
expected to induce a small but negative ΔS‡. Further experi-
ments were performed to deduce which unimolecular process,
prior to bimolecular Au(I/III) redox, is turnover-rate limiting.
Deuterium Kinetic Isotope Effects In order to probe the C-H
auration, a range of deuterated substrates were deployed in
intramolecular arylation, Scheme 4, equations 1-4. Control
experiments confirmed that there is no deuterium-protium
exchange before, during, or after cyclization, indicating that
Kinetics and Activation Parameters In our previous investiga-
tion of the intermolecular reaction (Scheme 2, upper), arene π-
complexation was found to be the turnover-limiting step, lead-
ing to pseudo first-order kinetics.9h By tethering the arene to the
arylsilane, and thus in turn to the aryl-gold, the effective molari-
ty of the arene is raised, potentially leading to the turnover lim-
iting step being driven to another stage in the cycle. Monitoring
overall C ̶ H / C ̶ D cleavage is irreversible. The absolute rates
of turnover of 4b versus d5-4b (Scheme 4, equation 1) were ex-
perimentally indistinguishable (kH/kD = 1.0). Thus the perdeu-
terated phenyl ring induces no significant primary or secondary
kinetic isotope effect (KIE) on the overall rate of catalytic turn-
over. This eliminates C-H cleavage from consideration as the
turnover-rate limiting step.
1
of the reaction of 4b by H NMR spectroscopy revealed the
expected9h induction period (approx 300 seconds) during which
the catalyst is converted to the tht-free active species LAuX3,
where L = MeOH, arene, or vacant site; X = CSA, and up to
one Br. After completion of the induction period, catalytic
turnover proceeds with clean pseudo-zero order kinetics, turn-
ing-over for the full reaction evolution at a formal frequency of
0.07 s-1 at 27 °C (Figure 1, top).
thtAuBr3
PhI(OAc)2 (1.1 equiv)
SiMe3
CSA (1.3 equiv)
1)
H4/D4
CHCl3/MeOH (50:1)
H5/D5
27 °C
5b/d4-5b
kH/kD=1.0
4b / d5-4b
thtAuBr3, 1.0 mol%
(indepdendent rate determinations)
SiMe3
PhI(OAc)2 (1.1 equiv.)
thtAuBr3
PhI(OAc)2 (1.1 equiv)
CSA (1.3 equiv)
CSA 2 (1.3 equiv.)
H/D
SiMe3
D
2)
CDCl3/CD3OD (50:1)
7 - 37 °C
4b
5b
CHCl3/MeOH (50:1)
rt
kH/kD=2.5
5b/d1-5b
d1-4b
D5
H5/D5
thtAuBr3
PhI(OAc)2 (1.1 equiv)
CSA (1.3 equiv)
Me3Si
3)
H4/D4
CHCl3/MeOH (50:1)
rt
10a
kH/kD=2.5
11a/a'
thtAuBr3
D
H/D
SiMe3
PhI(OAc)2 (1.1 equiv)
CSA (1.3 equiv)
O
O
4)
5)
CHCl3/MeOH (50:1)
rt
d1-4v
kH/kD=1.1
5v/d1-5v
R
R
thtAuBr3
PhI(OAc)2 (1.1 equiv)
CSA (1.3 equiv)
B
B
Me3Si
CHCl3/MeOH
rt
A
A
10b-f
11b-f
Major isomer when R = EWG
R = 3-Cl, 4-tBu, 4-F, 4-Cl, 4-CF3
Figure 1. Top: Pseudo-zero order kinetics for consumption of
4b in Au-catalyzed cyclization at 27 °C; d[4b]/dt = –kobst; where
–
1
kobs = 7×10-5 Ms ; R2 = 0.99. Bottom: Eyring analysis for cycliza-
Scheme 4. KIEs (1-4) and substituent partitioning (5) for intra-
molecular Au-catalyzed arylation.
tion of 4b (0.1 M) with 1 mol% Au, ln(k/T) = 34.54 – (12.86 ×
̶
103/T); R2 = 1.00; ΔH‡ = +26 kcal mol 1 and ΔS‡ = +21 e.u.
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Journal of the American Chemical Society
As noted by Schmidbaur, "η2-coordination to unsaturated
C-H Auration via SEAr versus CMD Having established that,
for 4b and 10a, C-H cleavage is irreversible and thus product-
determining (Scheme 4, equations 1-3), we studied intramolecu-
lar competition (10b-f) between electronically biased pairs of
arenes, equation 5. This allows distinction of reaction via a
monoaryl gold Wheland intermediate (SEAr) from C-H depro-
tonation of a π-complex (CMD), both leading to the same diaryl
gold intermediate. A large negative ρ value was obtained (ρ = –
3.7; see SI). In a concerted metalation-deprotonation (CMD)
the acidity of the proton is of importance20b and the net (nega-
tive) inductive effects of substituents dominate, leading to a
complex but overall positive ρ-correlation, which is not observed.
In contrast, stabilizing (positive) inductive and resonance effects
of substituents are expected to be of importance in an SEAr
process, leading to a negative ρ/ρ+-correlation.22
Turnover-limiting Reductive Elimination Reaction rates (Ms-1)
were determined under standard conditions (0.1 M substrate, 2
mol% thtAuBr3) for a series of 18 substrates in which the arene
(4a-m) or arylsilane (iso-4i-m) or bears a substituent that is meta
or para to the site of coupling in 5a-m, Figure 2. In addition to
singly substituted substrates, bis-silyl 12 and doubly-substituted
4t / 13 were also tested. The kinetics were analyzed by way of a
linear free-energy relationship (LFER) using the standard
Hammett σ-function, affording a reaction constant (ρ) of –2.0.
1
2
3
4
5
6
7
8
and aromatic hydrocarbons is the key step in gold-catalyzed
organic transformations",17 and gold(III) has a long history of
interacting with arenes. For example, it has been known for
over 80 years that anhydrous AuCl3 reacts readily with aromatic
hydrocarbons leading C-H auration of the arene.18 However, to
date, all attempts to experimentally prepare stable molecules
demonstrating Au•arene interactions have been unsuccessful.17
Nonetheless, such η2-arene gold(III) π-complexes species have
been explored computationally,19 and are implicated as precur-
sors to C-H auration. In our previous studies,9h this intermolecu-
lar π-complexation event was deduced to be turnover-rate limit-
ing, and the relative rates of arylation a series of arenes shown
to correlate with known stabilities of reference Ag-π-arene com-
plexes, and HF/BF3 Wheland-intermediates.9h However, there
was no indication from any of the data obtained, whether steps
prior to the irreversible C-H auration, are reversible or not.
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
The reversibility of the arene π-complexation can be tested
using the intramolecular cyclization. Thus although no KIE is
exhibited intermolecularly (4b versus d5-4b), an intramolecular
competition reaction employing d1-4b was found to elicit a sig-
nificant KIE (kH/kD = 2.5, equation 2) on the product distribu-
tion. In order for the primary KIE arising from C-H cleavage to
impact on the product distribution (5b versus d1-5b), the isoto-
pomeric precursor η2-complexes (8 and 9, Scheme 5) must be
able to equilibrate prior to irreversible, i.e. product-
SiMe3
RH
SiMe3
SiMe3
determining, C
within discrete Au-arene complexes (pathway A) or by reversible
η2-complexation (pathway B). The same primary KIE (kH/kD
̶ H / C ̶ D cleavage. Equilibration could occur
12 (R = H)
RSi
4t RSi = m-Me, RH = p-Me
13, RSi = p-Cl, RH = m-Cl
SiMe3
R
=
para
2.5) was obtained with bis-arene d5-10 (Scheme 4, equation 3)
confirming that Au-arene π-complexation is reversible, with C
H / C ̶ D cleavage being product-determining, but not turnover-
meta
H
̶
reductive
elimination (RE)
R
para
4a-m
R
[Au]III
meta
5a-m
rate limiting (no KIE, Scheme 4 equation 1).
SiMe3
a m-OMe; i p-OMe
b H; c t-Bu; h p-Me
d m-Cl; k p-Cl
e m-OPiv; i p-F
f m-CF3; l p-CF3
g m-OTf; m p OTf
R =
para
meta
H
H
14a-m
R
X
X
X
Pathway A
Pathway B
rate of RE
H
Au
D
para
D
Au
dependent only
on identity of R
X
R
X
X
iso-4i-m
9
8
p-OMe
p-OMe
2 x m-Me
m-t-Bu
D
p-Me
H
X
X
X
Au
H
m-OMe
p-F
m-Cl
p-Cl
H
H
δ–
R
iso-4i-m
X
p-CF3
δ+
R
X
2 x p-Cl
m-CF3
p-OTf
4a-m
[Au]
[Au]
p-OTf
p-CF3
SEAr
4t, 13
CMD
m-OTf
12
Scheme 5. η2-arene π-complexes and C-H auration mechanisms.
The KIEs outlined in equations 1-3 are consistent with both
a concerted metalation-deprotonation (CMD) pathway,20 and
an aromatic electrophilic substitution (SEAr) pathway,9h,18,21
both stemming from a presumed precursor η2-complex, Scheme
5. When the methylene bridge in d1-4b is replaced with an O-
atom linker, d1-4v, the primary KIE is nearly eliminated
(Scheme 4, equation 4), suggesting that the aryl-ether is able to
sufficiently stabilize the π-complex (CMD), or the Wheland
intermediate (SEAr) such that one of these two steps, rather
Figure 2. LFER analysis of rates of catalytic turnover during
cyclization of 4a-m; 4t, iso-4i-m, 12, and 13; log10 (kX /kH) = –
2.0 σ – 0.06;23 σ-values are additive for 4t/13. Conditions:
substrate (0.05 mmol), thtAuBr3 (2 mol%), 2-bromothiophene
(0.5 mmol),24 PhI(OAc)2 (0.055 mmol), CSA (0.065 mmol),
CDCl3/CD3OD (50:1, 0.1 M).
The correlation indicates that the impact of a substituent on
the rate of catalytic turnover is independent of its provenance;
i.e. whether it was initially on the arene (4a-m), the aryl-silane
than the C ̶ H / C ̶ D cleavage, becomes product-determining.
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Page 6 of 11
(iso-4i-m), or on both (4t, 13). This requires that the substrates
biaryl elimination proceeds.9g Thus overall, a very wide range of
1
2
3
4
5
6
7
8
converge on a common intermediate, at, or prior to, the turno-
ver-rate limiting step. This condition can be satisfied at any
point after C-H cleavage to generate a diaryl-gold intermediate.
Further evidence for convergence at a common intermediate
arises from the identical rates of turnover of bis-TMS 12 and
mono-TMS 4b (R = H), both of which generate 5b via reductive
elimination from the same intermediate (14b, Figure 2, R = H).
Reaction of bis-TMS 12 thus involves a second C-Si cleavage,
rather than C-H cleavage, at the stage of the mono-aryl-gold
intermediate. The selective intramolecular C-Si versus C-H au-
ration is again consistent with an SEAr process, with TMS-
stabilization of the β-cation in the Wheland intermediate being
favored.9h
rates have been determined for reductive R-R elimination from
gold (III) species, with a number of contributing factors, includ-
ing coordination number, formal charge, steric demand of lig-
ands, and the electron demand by the Ar / alkyl groups under-
going elimination. The turnover-rates of the intramolecular Au-
catalyzed process considered herein (up to 1 s-1, 27 °C, 4n, Ta-
ble 2) are significantly slower than that of the stoichiometric
reductive elimination from cationic [Ar2Au(PPh3)2]+, but not
dissimilar to that for the neutral complex [Ar2Au(PPh3)Cl].9g,30
Based on the kinetic studies of Kochi,29 the reductive elimi-
nation is expected to occur after ligand-dissociation from a neu-
tral four-coordinate precursor (15b, Figure 3, L = unspecified
neutral ligand, e.g. arene, solvent). 1H NMR spectroscopic anal-
ysis of the Au-catalyzed intramolecular arylation of 4b in CDCl3
/ CD3OD at 27 °C revealed a transient low-intensity methylene
signal, not attributable to traces of Ph2CH2 or catalyst-activation
co-products (see SI). The signal was tentatively assigned to the –
CH2– tether in 15b. Integration against an internal standard
allowed analysis of the temporal concentration of 15b, at three
different initial thtAuBr3 precatalyst loadings (1.0, 1.5 and 2.0
mol%), Figure 3.
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
The pseudo zero-order kinetics observed for of bis-TMS 12
and mono-TMS 4b limit the possibilities for a unimolecular
turnover-rate limiting step to reductive elimination from a di-
aryl-gold intermediate (14b), or ligand dissociation prior to
this.25 Reductive elimination is rarely the turnover limiting step
in C(sp2)-C(sp2) cross-coupling.26 In most cases, oxidative addi-
tion or transmetalation is rate-limiting. Indeed, as a conse-
quence of this, there has been a reliance on stoichiometric studies
to indirectly investigate reductive-elimination in catalytic sys-
tems.9g,9i,9j,27 Details relating to the kinetics and structures in-
volved in reductive elimination of a biaryl moiety from diaryl-
gold species are very sparse. There are very few examples of
isolated diaryl-gold complexes in which the aryls groups are
simple, i.e. non-chelating.9h,28 Nevado was able to isolate and
thtAuBr3 cat.
(1.0, 1.5, and 2.0 mol%)
PhI(OAc)2 (1.1 equiv.)
SiMe3
CSA 2 (1.3 equiv.)
CDCl3/CD3OD
(50:1), 27 °C
[Au]tot = 0.001; 0.0015; 0.002 M
4b
(0.1 M)
5b
characterize
(X-ray)9jk
the
neutral
di-aryl
complex
[Ar2Au(PPh3)Cl] where Ar = C6F5, and found that forcing con-
ditions were required to trigger reductive elimination of per-
fluorobiphenyl (150 °C, 20 h).9j
Pioneering studies by Kochi on trialkyl- and dialkyl-gold
phosphine complexes R3Au(PPh3) and R2Au(PPh3)X (where R =
Me, Et; X = Cl, TFA, NO3, OTf), revealed that that dissociation
of PPh3, leading to high-energy T-shaped species R3Au and
R2AuX, precedes reductive elimination of R-R.29 In most cases,
the overall rate of reductive elimination was slow (kobs = 10-6 to
10-7 s-1 at 45- 80 °C) and the liberated PPh3 progressively inhib-
ited reaction by disfavoring the dissociative pre-equilibrium.
The exception to this trend was Me2Au(PPh3)OTf, which reduc-
tively eliminated very rapidly (kobs >10s-1 at 25 °C). The possibil-
ity of an additional pathway for reductive elimination involving
triflate dissociation to generate cationic [Me2Au(PPh3)]+ could
not be discounted.29b
L
III
Au
X
15b
More recently, Toste has confirmed that, for specific cases,
phosphine dissociation is not necessary for reductive elimina-
tion to occur.9g The neutral complex [Ar2Au(PPh3)Cl], where Ar
= p-C6H4F, was generated in situ, and found to more efficiently
undergo reductive elimination (kobs = 10-4 s-1 at –52 °C) than the
analogous perfluoroaryl complex studied by Nevado.9j In con-
trast to the inhibiting effects of added phosphine noted by Ko-
chi, addition of PPh3, to generate the cationic bis(phosphine)
complex [Ar2Au(PPh3)2]+, resulted in substantial rate enhance-
ment (kobs = 0.2 s-1 at –52 °C). This process is “among the fastest
observed C–C bond-forming reductive couplings at any transi-
tion metal centre.”9g The high reaction velocity is ascribed to a
combination of Au(III)-destabilization by the formal cationic
charge at the gold, and the driving force provided by steric de-
compression of the bulky triphenyl phosphine ligands as the
Figure 3 Top: Pseudo-zero order kinetics (after induction peri-
od, approx. 300 sec.)9h for Au-catalyzed intramolecular arylation
of 4b using 1.0, 1.5 and 2.0 mol % Au. Middle: temporal turn-
over-rate of 4b /M s-1.31 Bottom: temporal concentration of
catalyst resting state, tentatively assigned as 15b; L = unspecified
neutral ligand, e.g. arene, solvent; X = unspecified anionic lig-
and.
Analysis of the steady-state maximum concentration of the
transient species (resting state, 15b; Figure 3, bottom) con-
firmed that it accounts for >90% of [Au]tot. Moreover, the con-
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Journal of the American Chemical Society
centration of 15b can be correlated with the temporal changes elimination will be reduced. Longer, non-rigid, tethers are ex-
in turnover-rate (–d[4b]/dt, Ms-1), Figure 3, middle. Thus the
during the induction period (approx 300 sec.) the concentra-
tion of 15b rises from zero to reach the steady-state, which is
maintained throughout the pseudo zero-order phase of turno-
ver. On complete consumption of substrate 4b, the concentra-
tion of 15b rapidly decays to zero.
pected to allow greater Au-Ar conformational mobility and thus
a lower energetic barrier to the attainment of the requisite face-
to-face orientation of the two aryl rings. However, longer tethers
will also reduce the effective molarity of the arene in the pre-
cursor C-H auration. The kinetics of cyclization of 4b (–CH2–
tether) are distinct from those of 4x (–CH2CH2– tether). In the
latter case, increase of the tether length by one methylene unit
results in a curved kinetic profile34 (Figure 4), indicative of a
mono-aryl-gold(III) resting state.9h
1
2
3
4
5
6
7
8
Effect of aryl electron-demand and Au-Ar conformational mobility
on Reductive-Elimination rates
The acceleration of reductive-
9
elimination by electron-donating substituents (ρ = –2.0; Figure
2) is partially consistent with literature precedent for other
Ar2[M] complexes (M = Pt, Pd), where electron-withdrawing
substituents are found to strengthen the ground-state metal-
carbon bonds.27b,32 Hartwig showed, from LFER analyses, that
reductive elimination from Ar2[Pt] “is faster from complexes
with a larger difference between the electron-donating proper-
ties of the two aryl groups.”27b,32 In other words, the electronic
effects of substituent on reductive elimination rates are not simp-
ly additive. In contrast, a recent computational study on reduc-
tive elimination from cis-[AuPPh3(Ar1)(Ar2)] complexes suggests
that the electronic effects of aryl substitution are additive.33 This
is now experimentally confirmed: disubstituted compounds 4t
and 13 generate di-aryl-gold intermediates that reductively elim-
inate at rates predicted by the sum of their σ-values (Figure 2).
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
SiMe3
thtAuBr3 (1 mol%)
PhI(OAc)2 (1.1 equiv)
CSA (1.3 equiv)
4b
5b
5x
CDCl3/CD3OD (50:1)
27 °C
SiMe3
as above
4x
0.1
0.08
0.06
0.04
0.02
0
Whilst most cyclizations gave pseudo-zero order profiles (e.g.
4b, Figure 3), the two slowest-reacting examples (p-CF3 4l, m-
OTF 4g, Figure 2), where the arene ring is substituted by elec-
tron-withdrawing groups, showed distinct curvature.34 This is
indicative of turnover-rate limiting arene π-complexation from
a mono-aryl-gold(III) resting state (17, Scheme 7),9h which was
tested by intermolecular interception of 17l with a π-rich arene,
resulting in co-generation of biaryl 16.35
4b
1500
4x
0
500
1000
Time/s
Figure 4. Turnover to generate 5- versus 6- membered rings.
Initial concentration of 4b and 4x 0.1 M. As reaction proceeds,
the turnover rate of 4x accelerates,34 becoming faster than that
of 4b.
[Au]
SiMe3
fast
A key observation is that as the reaction evolves, the rate of
turnover of 4x becomes faster than that of 4b, for which reduc-
tive-elimination is turnover-rate limiting. In other words, the
intrinsic rate of reductive-elimination from the longer –
CH2CH2– tethered intermediate 14x, must be faster than that
from the more constrained, –CH2– tethered, intermediate 14b
(Figure 5).36
iso-4l
iso-17l
CF3
CF3
CF3
CF3
Au
5l
(cis/trans)
15l resting state
L
X
SiMe3
[Au]
CF3
CF3
slow
4l
17l
resting state
Br
reductive
S
elimination
[Au]
14x (n = 2)
CF3
16
faster
kn=2
5x
5b
[Au]
[Au]
Scheme 7. Dependency of resting state identity (15 versus 17)
on the π-complexing ability of the arene. Conditions: 4l /iso-4l
(0.05 mmol), thtAuBr3 (2 mol%), PhI(OAc)2 (0.055 mmol),
CSA (0.065 mmol), CDCl3/CD3OD (50:1, 0.1 M), 2-
bromothiophene (0.5 mmol), 27 °C. See SI for an analysis of 5l
/ 16 partitioning as a function of conversion.
n
slower
kn=1
14b (n = 1)
Figure 5. Effect of tether length (n) and flexibility on Ar–Au–Ar
conformers from which developing Ar-Ar π-facial interaction28,33
can facilitate reductive elimination.
A normal primary KIE of 1.9 was obtained on intramolecular
competition using –CH2CH2– tethered d1-4x, indicative that
Wheland intermediate generation is partially reversible (Scheme
6). Once again, stabilization of the Wheland intermediate by
replacing the a CH2 linker by oxygen (d1-4aa) eliminates the
KIE. The impact of tether length (n = 1, 2) was further explored
by intramolecular competition using 18 (Scheme 7). The 5-
Calculations on reductive elimination from unconstrained28
[(Ar1)(Ar2)Au(PPh3)Cl] and [(Ar1)(Ar2)Au(PPh3)]+ complexes
show that the lowest energy transition state for involves Au-Ar
conformations in which the two aryl rings are oriented face-to-
face.33 If this arrangement is made less energetically accessible,
e.g. by strain, tethering or chelation,28 then rates of reductive
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Journal of the American Chemical Society
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membered ring cyclization outcompetes the 6-membered ring
steps39 in the intermolecular catalytic cycle, reductive elimina-
1
2
3
4
5
6
7
8
forming process by a factor of 13, consistent with selectivity-
determining, i.e. irreversible, C-H cleavage after Wheland inter-
mediate generation by ring A.37
tion from diaryl-gold(III) is fast. Consequently, it has not previ-
ously been possible to acquire kinetic data for this key C-C
bonding forming process. Application of the intramolecular
system has been pivotal in this regard. It allows two effects to be
used in concert: a) tethering the arene to the arylsilane induces
high effective molarity and raises the velocity of the C-H au-
ration step, whilst b) close-tethering of the aryls decreases the
velocity of the reductive elimination. In certain cases these two
effects (a,b) have been sufficient to move the catalyst resting
state to the diaryl-gold(III) intermediate, allowing a detailed
analysis of the influence of substituents on the rate of reductive
elimination.
thtAuBr3 (1 mol%)
D
PhI(OAc)2 (1.1 equiv)
CSA (1.3 equiv)
H/D
SiMe3
CHCl3/MeOH (50:1)
rt
kH/kD = 1.9
5x/ d1-5x
d1-4x
9
D
O
O
H/D
SiMe3
as above
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
kH/kD = 1.0
5aa/ d1-5aa
d1-4aa
thtAuBr3 (1 mol%)
PhI(OAc)2 (1.1 equiv)
CSA (1.3 equiv)
5
B
SiMe3
n
ArIX2
ArI
Bn
n
B
R1
R2
L
R2
Me3Si
I
L
X
X
Au
X
III
Au
A
+
X
CHCl3/MeOH (50:1)
rt
19 / 20 = 93 / 7
Ph
A
R1
TLS
4 and iso-4
19
20
18
when n = 1
TMS-X
[Au]
Step B
R2
Scheme 7. KIEs for 6-membered ring cyclization of 4x and 4aa,
and intramolecular competition (A versus B) to generate 5-
membered (19) versus 6-membered (20) rings.
n
resting state A
L
X
L
Au III
III
reductive elimination
Au
n
X
X
faster when n ≥2
accelerated by:
R1, R2 = EDG;
R1
n
15
R1
R2
17
resting state B
Conclusions
In 2012 we introduced a gold-catalyzed intermolecular direct
arylation reaction that uses arylsilanes to catalytically-generate
highly electrophilic Ar-Au intermediates capable of arylating
arenes at ambient temperature.5 The reaction has proven to be
a high-yielding, mild and efficient process for the coupling of a
wide variety of arylsilanes with electron-rich arenes and het-
eroarenes.5-8 Herein we have studied the intramolecular version
of the arylation, both as a preparative process, and as a vehicle
for mechanistic study. Using a standard set of conditions, 44-
examples of annelated-biaryls, with ring sizes ranging from 5- to
9-membered, including heteroatoms and a diverse range of
arene substituents, have been prepared under mild conditions
at ambient temperature (Table 2, Schemes 4, 6).38 Whilst the
majority of the reactions proceed with minimal side-product
generation, some highly electron-rich substrates are susceptible
to a competing direct reaction with the ArIX2 oxidant (HCIB,
2) to generate diaryliodonium salts. In such cases, PIFA (3) can
be used as a milder reagent to attenuate this undesired oxida-
tion. This effect is unique to the intramolecular process, and
facilitates the clean arylation of even highly electron-rich arenes,
such as the trimethoxy-benzene moiety of the allocolchinoid
skeleton 7,15 Scheme 3.
R2
Step A
R2
H
δ+
TLS when n ≥ 2,
or R2 = EWG (σ>0.43)
H
Au
L
X
III
n
n
[Au]
X
SEAr
R1
R1
Scheme 8. Mechanism of Au-catalyzed intramolecular aryla-
tion (4 → 5) with turnover-rate limiting step (TLS) proceeding
from a mono-aryl- (17) or di-aryl- (15) gold resting state, depend-
ing on tether-length (n), and electronic influence of arene sub-
stituent (R2). L = unspecified ligand: arene, solvent. X = CSA,
Br. For reductive elimination L = vacant site (14).
Using the unique features of the intramolecular variant of the
arylation process, we have been able to elucidate the following:
2
i) H-kinetic isotope effects (KIEs, Schemes 4 and 7) support
our previous conclusion5,9h that the C-H auration involves aro-
matic electrophilic substitution (SEAr)21 via a Wheland inter-
mediate, rather than a concerted metalation-deprotonation
(CMD) pathway.20
ii) When the aryl-arene tether is –CH2CH2–, despite the high
effective molarity of the arene, the C-H auration, beginning
with step A (Scheme 8), is the turnover-rate limiting step
(TLS).9h
Rendering the arylation process intramolecular induces a
number of changes that facilitate mechanistic investigation.
Firstly, unlike the intermolecular system, the vast majority of
the intramolecular substrates undergo turnover with simple and
reproducible kinetics, without complications from side reac-
tions such as arene oxidation or arylsilane homocoupling. Sec-
ondly, only electron rich arenes can be arylated intemolecularly,
limiting the range of arene substituents that can be explored in
linear free-energy relationships. In contrast, the intramolecular
system tolerates a wide range of arene substituents, both elec-
tron donating and electron withdrawing, and the kinetics have
been determined for substituents with σ-values ranging from –
0.3 to +0.6. Thirdly, relative to all of the other Au(III)-mediated
iii) Reduction of the tether length from –CH2CH2– to –CH2–
results in a migration of the turnover-rate limiting step (TLS)
from step A to step B, Scheme 8; but only when the arene is
sufficiently π-complexing (σ ≤0.43).
iv) Reductive-elimination from a diaryl-gold(III) intermediate
generates the biaryl product 5 (step B) and is accelerated by
electron-donating substituents (R1, R2) on the aryl rings. The
effect is independent of whether the substituent was originally
on the arylsilane or the arene ring. The acceleration correlates
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with standard σ-values for R1,R2, and if both rings are substitut-
Chem. Rev. 2011, 111, 1315–1345; d) Lyons, T. W.; Sanford, M.
ed, the effect is additive (σnet = σ-R1 + σ-R2).
S. Chem. Rev. 2010, 110, 1147–1169; e) Angew. Chem. Int. Ed.
2009, 48, 9792–9826; f) McGlacken, G. P.; Bateman, L. M.
Chem. Soc. Rev. 2009, 38, 2447–2464.
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v) There is a requirement for a face-to-face arrangement of the
two aryl rings during reductive elimination (step B). The short-
er –CH2– tether results in a slower rate of reductive elimination
compared to the longer –CH2CH2– unit, as the latter allows
greater conformational freedom for the system to attain the
required arrangement of the two aryl rings.
(4)
For reviews on gold catalysis, see: a) Pflasterer, D.; Hashmi, A.
S. K. Chem. Soc. Rev. 2016, 45, 1331–1367; b) Zi, W.; Toste, F.
D. Chem. Soc. Rev. 2016, 45, 4567–4589; c) Zheng, Z.; Wang,
Z.; Wang, Y.; Zhang, L. Chem. Soc. Rev. 2016, 45, 4448–4458;
d) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028–
9072; e) Deharo, T.; Nevado, C. Synthesis 2011, 2530–2539; f)
Wegner, H. A.; Auzias, M. Angew. Chem. Int. Ed. 2011, 50,
8236–8247; g) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180–
3211; h) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Commun.
2007, 4, 333–346; i) Hashmi, A. S. K.; Hutchings, G. J. Angew.
Chem. Int. Ed. 2006, 45, 7896–7936.
Ball, L. T.; Lloyd-Jones, G. C.; Russell, C. A. Science 2012, 337,
1644–1648.
Hata, K.; Ito, H.; Segawa, Y.; Itami, K. Beilstein J. Org. Chem.
2015, 11, 2737–2746.
Hua, Y.; Asgari, P.; Avullala, T.; Jeon, J. J. Am. Chem. Soc. 2016,
138, 7982–7991.
In summary, the investigation of catalytic reaction mechanism
plays an important role in the discovery and development of
new synthetic methodology. It can lead to useful generalizations
and design principles in the optimization and application of
catalysis. However, mechanistic studies are often limited to a
small collection of well-behaved substrates, or constrained to a
narrow range of accessible reaction conditions. In such cases,
mechanistic insight must be extrapolated with caution, even for
what may appear to be a closely related system: the assumption
that the same parameters and constraints apply, may not be
valid. The results presented herein demonstrate exactly such a
situation. Even small changes in the substrate structure lead to
different mechanistic behaviors. Thus by changing a single aryl
substituent from being above or below σ = 0.43, or by varying
the tether length by one methylene unit, the catalyst resting
state can switch from one side of the cycle to the other (A ver-
sus B, Scheme 8). The last step of the cycle, the Au(I)/Au(III)
redox by ArIX2 reagents (e.g. 2 and 3), remains one for which
there is very little mechanistic detail. Rapid redox is essential
for the success of the reaction;39 this process is under active
investigation.
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(6)
(7)
(8)
(9)
Cresswell, A. J.; Lloyd-Jones, G. C. Chem. Eur. J. 2016, 22,
12641–12645.
For reviews on reactivity and isolation of gold complexes, see:
a) Joost, M.; Amgoune, A.; Bourissou, D. Angew. Chem. Int. Ed.
2015, 54, 15022–15045; b) Hashmi, A. S. K. Angew. Chemie Int.
Ed. 2010, 49, 5232–5241. For selected recent advances in the
field, see: c) Kawai, H.; Wolf, W. J.; DiPasquale, A. G.; Winston,
M. S.; Toste, F. D. J. Am. Chem. Soc. 2016, 138, 587–593; d)
Joost, M.; Estévez, L.; Miqueu, K.; Amgoune, A.; Bourissou, D.
Angew. Chem. Int. Ed. 2015, 54, 5236–5240; e) Winston, M. S.;
Wolf, W. J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137, 7921–
7928; f) Wu, C.-Y.; Horibe, T.; Jacobsen, C. B.; Toste, F. D.
Nature 2015, 517, 449–454; g) Wolf, W. J.; Winston, M. S.;
Toste, F. D. Nat. Chem. 2014, 6, 159–164; h) Ball, L. T.; Lloyd-
Jones, G. C.; Russell, C. A. J. Am. Chem. Soc. 2014, 136, 254–
264; i) Wu, Q.; Du, C.; Huang, Y.; Liu, X.; Long, Z.; Song, F.;
You, J. Chem. Sci. 2014, 6, 288–293; j) Hofer, M.; Gomez-
Bengoa, E.; Nevado, C. Organometallics 2014, 33, 1328–1332; k)
Hofer, M.; Nevado, C. Eur. J. Inorg. Chem. 2012, 1338− 1341.
For pioneering studies into intramolecular direct arylation, see:
a) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008, 64,
6015–6020; b) Campeau, L. C.; Parisien, M.; Jean, A.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 581–590. c) Campeau, L. C.;
Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc. 2004,
126, 9186–9187.
For select examples of 7-, 8- and 9- membered ring synthesis
via direct arylation, see: a) Pintori, D. G.; Greaney, M. F. J. Am.
Chem. Soc. 2011, 133, 1209–1211; b) Majumdar, K. C.; Ray, K.;
Ganai, S. Tetrahedron Lett. 2010, 51, 1736–1738; c)
Blaszykowski, C.; Aktoudianakis, E.; Alberico, D.; Bressy, C.;
Hulcoop, D. G.; Jafarpour, F.; Joushaghani, A.; Laleu, B.;
Lautens, M. J. Org. Chem. 2008, 73, 1888–1897; d) Beccalli, E.
M.; Broggini, G.; Martinelli, M.; Paladino, G.; Rossi, E. Synthesis
2006, 2404–2412; e) Bressy, C.; Alberico, D.; Lautens, M. J. Am.
Chem. Soc. 2005, 127, 13148; f) Leblanc, M.; Fagnou, K. Org.
Lett. 2005, 7, 2849–2852; g) Bowie, A. L.; Hughes, C. C.;
Trauner, D. Org. Lett. 2005, 7, 5207–5209; h) Kozikowski, A. P.;
Ma, D. Tetrahedron Lett. 1991, 32, 3317.
ASSOCIATED CONTENT
Additional discussion, experimental procedures, kinetic data,
characterization data, and NMR spectra. This material is availa-
ble free of charge via the internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
guy.lloyd-jones@ed.ac.uk
Notes The authors declare no competing financial interest.
Funding Sources The research leading to these results has re-
ceived funding from the European Research Council under the
European Union's Seventh Framework Programme (FP7/2007-
2013) / ERC grant agreement n° [340163].
REFERENCES
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Increased yields are only obtained with the most electron-rich
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intermolecular examples; presumably because it does not
release a strong-enough acid (such as CSA) to catalyze the
methanol-dissociation for π-complexation / C-H auration.9h
For examples of syntheses of this scaffold, see: a) Djurdjevic,
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Hussain, I.; Singh, T. Adv. Synth. Catal. 2014, 356, 1661–1696
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Reductive elmination from chelated Ph-Au(X)-(Ar-N-donor)
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Vicente, J.; Dolores Bermudez, M.; Escribano, J.
Organometallics 1991, 10, 3380–3384; see also reference 9i
a) Komiya, S.; Albright, T. A.; Hoffmann, R.; Kochi, J. K. J. Am.
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Use of the reported activation parameters (ref 9g) for
Ar2Au(PPh3)Cl, indicates that the rate of reductive elimination
of this system at 27 °C is about 5 s-1.
Turnover rates were estimated by differentiation of high-order
polynomial fits to the temporal concentration plots.
Hartwig, J. F. Inorg. Chem. 2007, 46, 1936–1947.
a) Nijamudheen, A.; Karmakar, S.; Datta, A. Chem. Eur. J. 2014,
20, 14650–14658.
Rates for these substrates are dependent on the CSA
concentration, see SI, which rises as oxidant (2) is consumed.
The curvature does not arise from a longer induction period;
pre-catalyst activation is complete in around 300 seconds9h
(based on analysis of Ar-Br co-products, see SI) this being less
than 2% of the time taken for complete turnover of the
substrate.
Control experiments confirmed that the pseudo-zero order
rate profile for cyclization of iso-4l is independent of CSA
concentration, consistent with turnover of iso-4l via reductive
elimination from the normal diaryl gold (15l) resting state. For
systems bearing a –CH2– tether, the transition from di- to
mono-aryl-gold resting state is only observed for examples 4l
and 4g, where the arene ring bears strongly electron-
withdrawing groups (σnet ≥0.43). Bromothiophene-trapped
products were not obtained with any substrates where σnet
<0.43.
At this stage we cannot assess how much faster the reductive
elimination to the 6-membered ring is, as the change in kinetic
profile also suggests a change in the TLS; thus turnover-rate
may be limited by π-complexation or reductive elimination, or
both, at different stages in the reaction evolution.
This selectivity may arise from the differential developing
strain in 6-membered versus 7-membered aurocycles
generated from rings A / B respectively.
3
4
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5
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6
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8
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Ghosh, M. K.; Tilset, M.; Venugopal, A.; Heyn, R.; Swang, O. J.
Phys. Chem. A 2010, 114, 8135–8141.
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Org. Chem. 2012, 77, 658–668; b) García-Cuadrado, D.; de
Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J.
Am. Chem. Soc. 2007, 129, 6880–6886. For a perspective on
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Livendahl, M.; Echavarren, A. M. Isr. J. Chem. 2010, 50, 630–
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gold, see: a) Kharasch, M. S.; Beck, T. M. J. Am. Chem. Soc.
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X. C.; Boorman, T. C.; Lu, P.; Larrosa, I. Angew. Chem. Int. Ed.
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Cambeiro, X. C.; Ahlsten, N.; Larrosa, I. J. Am. Chem. Soc. 2015,
137, 15636–15639. See also ref 9h.
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(22)
A 'normal' ρ value would be expected for π-complexation,
whereas
a
ρ+ value would be expected for Wheland
intermediate generation, see reference 9h. The KIEs obtained
with 10a indicate π-complexation is reversible for simple
phenyl rings. However, the rate data do not give an ideal linear
correlation, and the electronically biased rings in 10b-f may
shift the process away from Curtin-Hammett control such that
the ratios begin to reflect the equilibrium population.
(38)
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This applies to all but 4ai (Table 2, entry 18) which required
heating to 50 °C.
If the Au(I)X / Au(III)X3 redox it is not sufficiently rapid (due to
low oxidant concentration or kinetically-ineffective oxidant
species) the Au(I) disproportionates, resulting in rapid catalyst
deactivation.
(23)
(24)
Standard Hammett σ-values were employed (Hansch, C.; Leo,
A.; Taft, R. W. Chem. Rev. 1991, 91, 165− 195) except for the
value for p-F where, in our experience, σp = 0.15 (Shulgin, A. T.;
Baker, A. W. Nature, 1958, 182, 1299) is better parameterized
for reactions in non-aqueous media, as compared to the
standard value of σp = 0.06 which was determined in water.
Kinetic profiles obtained with electron deficient arylsilanes
were partially non-linear, this was resolved by addition of 2-
bromothiophene. The detailed kinetics of this phenomenon
are currently under investigation. Arenes 4l (p-CF3) and 4g (m-
OTf) also gave curved kinetic profiles (i.e. imperfect pseudo
zero order kinetics) that were not linearized by addition 2-
bromothiophene. The rate averages were employed for the
correlation, and are slightly lower than predicted by log10(kX
/kH) = –2.0ρ – 0.06. See Figure 6 and associated text for more
detailed discussion, and SI for rate limits.
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The large ΔS‡ value (Fig 1) may be an apparent activatiton
parameter, arising from combination of a pre-equilibrium
dissociation with irreversible reductive elimination from a
three-coordinate intermediate.
(26)
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Graphic entry for the Table of Contents (TOC).
5
6
7
Typically:
1−2 mol% Au
[oxidant]
5−9
8
9
21-27 °C
10 min−16 hours
SiMe3
H
36 preparative
examples
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via
[Au]
fast reductive elimination
when R or R' = EDG and
tether is flexible
6−10
R
R'
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