Au-Catalyzed Oxidative Arylation: Chelation-Induced Turnover of ortho-Substituted Arylsilanes

Article abstract of DOI:10.1021/acscatal.8b02302

ortho-Substituted aryl silanes have previously been found to undergo much slower Au-catalyzed intermolecular arylation than their m,p-substituted isomers, with many examples failing to undergo turnover at all. A method to indirectly quantify the rates of C-Si auration of o-substituted aryl silanes, under conditions of turnover, has been developed. All examples are found to undergo very efficient C-Si auration, indicative that it is the subsequent C-H auration that is inhibited by the ortho substituent. A simple Ar-Au conformational model suggests that C-H auration can be accelerated by chelation. A series of ortho-functionalized aryl silanes are shown to undergo efficient arylation.

Full text of DOI:10.1021/acscatal.8b02302

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Letter
Au-Catalyzed Oxidative Arylation: Chelation-
Induced Turnover of ortho-Substituted Arylsilanes
Matthew P. Robinson, and Guy C. Lloyd-Jones
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02302 • Publication Date (Web): 17 Jul 2018
Downloaded from http://pubs.acs.org on July 17, 2018
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ACS Catalysis
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Au-Catalyzed Oxidative Arylation: Chelation-Induced Turnover of
ortho-Substituted Arylsilanes
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Matthew P. Robinson and Guy C. Lloyd-Jones*
EaStChem, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh, EH9 3FJ, UK.
KEYWORDS Gold-catalysis, Mechanism, C–H Arylation, Rate-attenuation Analysis, Ortho-substituents
ABSTRACT: Ortho-substituted aryl silanes have previously been found to undergo much slower Au-catalyzed intermo-
lecular arylation than their m,p-substituted isomers, with many examples failing to undergo turnover at all. A method to
indirectly quantify the rates of C–Si auration of o-substituted aryl silanes, under conditions of turnover, has been devel-
oped. All examples are found to undergo very efficient C–Si auration, indicative that it is the subsequent C–H auration
that is inhibited by the ortho substituent. A simple Ar-Au conformational model suggests that C–H auration can be
accelerated by chelation. A series of ortho-functionalized aryl silanes are shown to undergo efficient arylation.
Introduction
1 in Au-catalyzed arylation and show that efficient
coupling can be induced by o-functionalization.
Organosilanes are an attractive class of reagent for
ArIX2
1
Ar Ar
transition metal catalyzed couplings, with benefits of
L AuI
X
3
1g
high stability, ease of preparation, and low toxicity. The
ArI
k7,4
k6,7
7
2
3
gold-catalyzed direct arylation of aryltrimethylsilanes
ArIX2
Ar
Ar
L
X
AuIII
X
X
X
L
AuIII
tht.AuBr3
(1) with π-rich arenes (2) to afford biaryls (3) was first
6
(1, 2)
4
4
reported 2012. The reaction can be conducted under air,
k5,6
k4,5
using laboratory grade solvent (CHCl
3
/MeOH), often at
HX
Ar SiMe3
1
ambient temperature, and around 160 examples have
L
X
X
AuIII
Ar
H
Me3SiX
Ar
4-8
5-7
been published to date. Mechanistic studies indicate
that turnover proceeds via sequential electrophilic
5
2
[Au] cat. (1-2 mol%)
CSA (1.5 equiv)
PhIX2 (1.3 equiv)
aromatic aurations (S
(k5,6), followed by reductive elimination (k6,7
E
Ar) of the silane (k4,5), then the arene
SiMe3
+
R2
R2
R1
)
and
R1
CHCl3 / MeOH (50:1)
> 90 %
H
Au(I)/I(III) redox (k7,4) Scheme 1. For the vast majority of
cases, the turnover-rate limiting event is intermolecular
C-H arylation (k5,6), proceeding with a first-order kinetic
1
2
3
temp / time
Br
Br
Ar
OMe
Br
OMe
Br
S
Me
S
F
Ar
5
dependence on 2 and a negative entropy of activation.
Me
F
Whilst the substrate scope for the coupling has proven
21 °C, 8h.
21 °C, 33 h.
21 °C, 30 h.
65 °C, 36 h.
4-8
to be reasonably broad, ortho-substituted arylsilanes (o-
[a] Au cat = (Ph3P)AuOTs or tht.AuBr3. CSA = camphor sulfonic acid. PhIX2 = PhI(OAc)2
(IBDA) or 1-hydroxy-1,2-benziodoxol-3-(1H)-one) (IBA); 1-2 equiv. 2. Ar = 4-F-C6H4.
1) undergo slow intermolecular coupling, requiring
Scheme 1. General catalytic cycle for Au-catalyzed
prolonged reaction times or elevated temperatures,
4,5,8b
arylation, and comparison of conditions for arylation of
Scheme 1.
Indeed, a number of examples of hindered
a
ortho- versus para-ArSiMe (o/p-1).
3
ortho-substituted arylsilanes fail to couple at all. In
contrast, substituted arenes (2) can be efficiently coupled,
even though these must also generate a sterically-
hindered diaryl-gold intermediate, 6. The slow rates of
Discussion
We began by testing how steric hindrance affects the C–
Si auration (k4,5) of the arylsilane, comparing the relative
rates of a small series of o-alkyl arylsilanes (o-1a-j) under
arylation of o-1 also contrast other S
protodesilylation, and mercuridesilylation,
E
Ar processes, e.g.
9
10
where
catalytic
conditions.
Conventional
competition
ortho-substituted arylsilanes react significantly faster
than predicted based on the inductive effect of the
substituents alone. Herein we analyze the reactivity of o-
experiments determine relative rates (krel) for a pair of
substrates by monitoring their ratio as a function of their
conversion to product. However, this cannot be
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ACS Catalysis
employed with the many examples of o-1 that do not
undergo turnover to product. We therefore developed an
alternative approach that solely analyzes the effect of o-1
on the kinetics of another substrate that does undergo
turnover. The intramolecular coupling of 1a to form
Page 2 of 6
thtAuBr3 (2 mol%)
IBDA (1.3 equiv)
CSA (1.5 equiv)
[Au]
SiMe3
R
R
1
2
3
4
5
6
7
8
CDCl3 / CD3OD
(50:1), 21 °C
o-1b-j
o-5b-j
krel by competition with o-1a
SiMe3
Me
SiMe3
Et
SiMe3
SiMe3
Cy
SiMe3
t-Bu
SiMe3
Ph
fluorene (3a, Figure 1) proved ideal.
i-Pr
SiMe3
Me
0-10 mol %
[Au] o-5b
o-1g
o-1b
o-1c
o-1d
o-1e
o-1f
krel = 2.9
o-1b
Me
SiMe3
k
rel = 1.2 krel = 1.5
krel = 1.3
krel = 1.3
krel = 1.0
9
2 mol % Au
SiMe2Et
SiEt3
SiMe3
Me
SiMe3
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SiMe3
Me
Me
Bn
oxidant
21 °C
inhibition
Me
3a
1a, 0.1 M
Me
pseudo zero order kinetics with 0 mol % o-1b
o,o-1j
krel = 2.1
p-1b
krel = <0.05b
o-1h
o-1i
o-1a
krel = 1c
krel = 0.7 krel = 0.2
Ar
Ar
rate of 3a
generation
attenuated
by o-1
ArIX2
k7,4
L AuI
X
[a] Determined by simulation of rate-attenuation for turnover of 1a to 3a, see
Figure 1. Temporal concentrations analyzed in situ by 1H NMR. [b] measured
by competition with o-1b, see reference 5 [c] by definition, krel = 1.
3a
o-1
ArI
k6,7
7
Ar SiMe3
Ar
L
X
AuIII
X
X
X
X
X
L
AuIII
L
Ar
AuIII
Ar
6a
k4,5 (o-1)
4
resting
state
a
o-5
Scheme 2. Relative rates of C–Si auration (k4,5) for o-1b-j.
k5,6
inhibition
k4,5 (1a)
HX
Ar SiMe3
9
The acceleration of aryl silane protodesilylation, and
L
X
X
AuIII
5a
Ar
1a
H
Ar
10
mercuridesilylation, by ortho-methyl substituents arises
Ar
H
from alleviation of ground-state steric strain on approach
9,10,12
with o-1b:
2.5 mol %
to a pseudo-tetrahedral Wheland intermediate.
An
Ar
Ar
3a
0.10
analogous effect in C–Si auration (k4,5), Figure 2A, may
explain why o-1b reacts more than twenty-fold faster than
p-1b (Scheme 2). The similar rates of C–Si auration of the
ortho-benzyl, -methyl, -ethyl, -isopropyl, and -cyclohexyl
substrates (o-1a-e) will arise from a combination of effects,
k4,5 [o-1b]
k4,5 [1a]
0.08
0.06
0.04
0.02
0.00
krel
=
= 1.2
5.0 mol %
7.5 mol %
10 mol %
including access to Ar-CHR
2
conformations that
minimize steric compression with the silane (such a
conformation is absent in the fastest reacting substrate o-
1f), steric interaction with the incoming Au-electrophile,
Figure 2B, and steric shielding of the charge-polarized
Wheland intermediate from solvation. Analogous steric
0
1000
2000
3000
time / s
[a] conditions: CSA 0.15 M, PhI(OAc)2 0.13 M, CDCl3 / CD3OD (50 / 1), 21 °C.
Evolution of 3a analyzed in situ by 1H NMR (CH2).
a
Figure 1. Rate-attenuation analysis to determine krel
.
interactions attenuate the rate of protodesilylation of
13
ArSiR
3
species with larger Si-substituents. The EtMe
2Si
In the absence of competitor (o-1), the cyclization of 1a
to 3a proceeds to completion, with clean pseudo-zero
order kinetics, in about 15 minutes (2 mol% cat., 21 °C).
Any factor that causes a decrease in the active catalyst
concentration over the course of the reaction leads to
and Et
3
Si substrates o-1h,i behave accordingly, Figure 2C.
A
+
+
[Au]
[Au]
k4,5
Me
Me3Si
Me
[Au]
Me
+
Me3Si
Me3SiX
o-1b
o-5b
+
+
11
[Au]
R
curvature in the temporal concentration profile. The rate
[Au]
B
C
R
H
of generation of 3a is thus attenuated by competing C–Si
auration (k4,5) of o-1. The rate-attenuation depends on the
reactivity of o-1 (k4,5) and the concentration of o-1, relative
to 1a. An example analysis for o-1b is shown in Figure 1.
The onset of rate-attenuation for generation of 3a becomes
increasingly evident as the inhibitor concentration is
raised (0, 2.5, 5, 7.5, 10 mol %). Kinetic simulation of the
evolution of 3a, with inclusion of pre-catalyst activation
and turnover, see SI, allows extraction of the relative rates
of C–Si auration (k4,5) for the series o-1b-j, Scheme 2. It is
notable that all of the examples in the series, including
Me
R
Si
Me3Si
R
R
o-1h,i
o-1a-e
Figure 2. A. steric decompression during electrophilic
auration (k4,5) of o-1b. B. Similar reactivities of ortho
methyl, ethyl, isopropyl and cyclohexyl substrates o-1b-e.
C. Reduction in reactivity of ArSiMe
2
Et and ArSiEt o-1hi.
3
Since the rate attenuation analysis (Scheme 2) shows
that all of the o-arylsilanes undergo efficient C–Si auration
14
(k4,5), the inhibiting effect of the ortho-substituent on the
sterically hindered o-tBu 1f and 2,6-Me
2
1j, undergo more
rapid C–Si auration (k4,5) than unhindered para-1b.
overall coupling (1 ®6) is therefore not manifest until the
subsequent step: the C–H auration of o-5 (k5,6). In our
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Page 3 of 6
ACS Catalysis
previous mechanistic studies on the cyclization of 1a we
smoothly at ambient temperature at a similar rate to p-1b,
1
2
3
4
5
6
7
8
found that, unusually, the turnover-rate limiting event is
reductive elimination from the corresponding biaryl
intermediate 6a, leading to pseudo zero-order kinetics
Scheme 3.
Br
Br
thtAuBr3
S
(2 mol%)
HCIB
S
SiMe3
[Au]
6
k5,6
R
(Figure 1). Consideration of the conformational
(1.3 equiv)a
R
H
R
equilibrium around the Ar-Au bond in the mono-aryl
precursor 5a suggests that a perpendicular arrangement of
the benzyl group to the square-plane of ligands at gold
(5aper) will be favored, on steric grounds, over a coplanar
arrangement (5aco), Figure 3.
-HX, [AuI]
CDCl3 / CD3OD
(50:1) 21 °C
o-1
o-5
o-3
krel (intermolecular turnover)b
SiMe3
9
SiMe3
Me
SiMe3
SiMe3
SiMe3
Et
t-Bu
10
11
12
13
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15
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OH
intramolecular
arylation
Me
Kco
p-1bc
o-1b
o-1c
o-1f
no reaction
o-1k
X
L
H
X
Ph
Au
krel = 20
krel = 4
krel = 2.5
krel = 14
X
L
X
k5,6
Au
L
Au
X
OH
SiMe3
SiMe3
SiMe3
SiMe3
Me Me
– HX
SiEt3
6a
5aco
5aper
OH
OH
Me Me
Me Me
OH
OH
(2)
o-1md
krel = 22
o-1p
(2)
o-1l
o-1n
o-1o
krel = 14
krel = 24
krel = 3.5
krel = 15
H
R
H
Kco
slow
X
L
L
X
X
SiMe3
SiMe3
o-6
SiMe3
SiMe3
Au
R
Au
X
k
5,6 (2)
OH
OMe
– HX
o-5per
o-5co
Me Me
OMe
OMe
o-1q
rel = 1
o-1r
krel = 475
o-1s
krel = 265
o-1t
krel = 7
k
(2)
(2)
L
[a] [hydroxy(camphorsulfonyloxy)iodo]benzene. [b] krel estimated from initial rates:
d[3]/dt = k5,6[Au]0[Ar-H]0. [c] data from reference 5; [d] stalled at 50 % conversion.
chelation
Kco
H
fast
H
X
X
L
L
X
X
o-6
Au
Au
k
5,6 (2)
Scheme 3. Relative rates of intermolecular arylation (k5,6
of o-5 by 2-bromothiophene.
)
– HX
o-5per
o-5co
Figure 3. Conformations of Ar-Au intermediates (o-5co / o-
per) leading to arylation (k5,6) and the impact of chelation.
Unsurprisingly, the nature of the tether, e.g.
coordinating ability, chelate ring size, and substitution
pattern (steric effects), strongly impacts the rate of
turnover. Detailed analysis is complex as the overall effect
will arise though changes in chelate equilibrium (Kco) and
the efficiency of coordination of the incoming arene (k5,6).
For example, addition of methyl substituents (o-1o-q)
does not reduce turnover as much as might be
5
Arrangement 5aper allows the benzyl group to undergo
associative p-complexation then C-H auration (k5,6) to
access the resting state (6a). In contrast to 5a,
14
intermediates of the type 5b-f,h-j must undergo
turnover-rate limiting intermolecular associative p-
5,6
complexation to effect arylation (k5,6). Conformer o-5per
16
anticipated, possibly due to a gem-disubstituent effect
15
will be significantly less accessible to the incoming arene
biasing Kco. In contrast, the o-alkoxymethyl series (o-1r-t)
induce a significant increase in turnover rate, with o-1r
undergoing coupling >20-fold faster than p-1b. The
marked difference in turnover rate between pairs of
alcohols o-1k,n and ethers o-1r,s suggests that shorter
tether neutral two-electron (L-type) ligation, rather than
X-type, provides the greater overall activating effect (Kco
and k5,6). The rates for the trimethylsilyl (o-1k) and
triethylsilyl (o-1l) substrates were identical, despite o-1k
undergoing addition (k4,5) to Au approximately 5-fold
faster than o-1l, Scheme 2. This result is consistent with
turnover-rate limiting intermolecular arylation (k5,6), i.e.
both substrates converge on the same aryl-Au
intermediate (5k = 5l). A selection of the more-efficient
substrates from Scheme 3 (o-1k; o-1mn; o-1rs) plus a small
(2) than o-5co. Thus, the more sterically imposing the ortho-
substituent, the further the equilibrium (Kco) will biased
toward o-5per and the greater the suppression of the rate of
turnover. We have previously shown that the electronic
influence of m- and p-arylsilane substituents on the rate of
5
turnover is negligible (r = –0.2). The conformational
equilibrium (Kco), and steric shielding effect (o-5per) thus
provides a simple explanation for the five-fold faster
turnover of p-1b by 2-bromothiophene compared to o-1b,
Scheme 3. The rate is further suppressed by Et (o-1c), with
complete inhibition of turnover by tBu (o-1f), despite the
latter undergoing the fastest C-Si auration (Scheme 2).
15
The o-Au-Ar conformational model suggests that the
5,6
rate of arylation (k5,6), and thus net rate of turnover, can
be accelerated by using chelation to bias the equilibrium
toward the reactive species, 5co. Introduction of ortho-n-
alkylhydroxy groups (o-1k-n) resulted in an increase in
turnover rate for intermolecular coupling, reacting
17
range of other functional groups were then explored for
preparative arylation; isolated yields of the coupling
products (o-3a-ai; 1 mmol scale) are shown in Scheme 4.
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Page 4 of 6
2-Br-thiophene
(1 equiv.)
substrates failing to turn-over at all. Herein, we employed
rate-attenuation analysis, Figure 1, to confirm that the C-
Si auration step (k4,5) is significantly accelerated by
substitution at the ortho-position, even with sterically-
demanding substituents, Scheme 2. The effect is
Br
1
2
3
4
5
6
7
8
11
thtAuBr3 (2 mol%)
HCIB (1.3 equiv)a
SiMe3
S
R
R
CHCl3 / MeOH (50:1)
21 °C, (time)
o-3
o-1
Ar
OMe
OH Ar
Ar
Ar
Ar
analogous to other S Ar reactions of ortho-arylsilanes,
E
OMe
OH
OH
where there is alleviation of steric strain upon formation
9,10,12,13
of the Wheland intermediate.
(16 h.)
(12 h.)
(16 h.)
(1 h.)
(10 h.)
o-3s
95%
o-3k
o-3m
o-3n
o-3r
90%
78%b,c,d
79%b,e
80%
9
The marked reduction, or complete inhibition, of
turnover by simple ortho substituents (e.g. o-1f, Scheme 3)
arises from the impact of the substituent on the
subsequent C-H auration step (k5,6). A model involving
t-Bu
Ar
O
S
Ar
Ar
O
Ar
O
O
O
O
Ar
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12
13
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S
S
PPh2
O
Me
NEt2
Me
Me
o-3x
79%
(12 h.)
(16 h.)
(16 h.)
(16 h.)
o-3y (16 h.)
o-3u
o-3v
o-3w
86%
Ar
91%
75%
80%
two conformations of the aryl-Au intermediate 5, with
15
OMe
Ar
steric shielding arising in the dominant conformer 5co
,
Ar
Ar
OMe
Ar
CO2Me
NEt2
O
O
Me
Figure 3, accounts for the inhibiting effect of o-alkyl
OPiv
14
substituents. Based on the model, ortho-chelation should
SiMe3
(10 h.)
increase the population of the reactive co-planar
conformer 5co. A diverse range of synthetically-useful
functional groups allow the arylated products to be
obtained in good yield (Scheme 4). Of the carefully
(16 h.)
(16 h.)
(16 h.)
(16 h.)
o-3ad
70%b,f
o-3z
o-3aa
o-3ab
o-3ac
73%
77%
83%
51%
Ar-H (1 equiv.)
thtAuBr3 (2 mol%)
HCIB (1.3 equiv)a
SiMe3
Ar
OMe
17
OMe
selected range of functional groups tested, short-
CHCl3 / MeOH (50:1)
21 °C, (time)
chained methyl ethers, e.g. o-1r-u, induced the fastest
rates of arylation.
o-1r
Me
Me
Me
Br
Br
Br
Me
OMe
The above observations regarding the importance of
Ar-Au conformation in the Au-catalyzed oxidative
arylation of aryl silanes (Scheme 1), and the ability to bias
this by chelation (Scheme 3) can be applied in the analysis
and development of the wide range of other catalyzed
S
S
Br
OMe
OMe
Me Me
OMe
Me
OMe
o-3af
83%
o-3ai g
(16 h.)
(12 h.)
o-3ag (24 h.)
77%
(36 h.)
o-3ah
31%
o-3ae
76%
0%
2,19
reactions involving aryl-gold intermediates.
[a] [hydroxy(camphorsulfonyloxy)iodo]benzene [b] 2 equiv 2-bromothiophene; [c] With 1
equiv 2-bromothiophene 60% yield; [d] Triethylsilyl analogue o-1l gave 67% yield; [e]
With 1 equiv 2-bromothiophene 54% yield; [f] Purity estimated to be 90% by 1H NMR. [g]
no products detected, other than initial bromodesilylation of o-1r, after 40 h.
AUTHOR INFORMATION
Corresponding Author
Scheme 4. Preparative arylation of o-aryl silanes.
The majority of the potentially-coordinating ortho-
* guy.lloyd-jones@ed.ac.uk
Funding Sources
17
substituents tested, including ethers (o-1u), esters (o-1aa,
The research leading to these results has received funding
from the European Research Council under the European
Union's Seventh Framework Programme (FP7/2007-2013) /
ERC grant agreement n° [340163].
o-1ab), a carbamate (o-1z), various sulfur-containing
functional groups (o-1v-x), and a phosphine oxide, (o-1y)
induced efficient intermolecular coupling, at ambient
temperature. A small number of ortho-substituents that
ASSOCIATED CONTENT
were
tested
underwent
competing
solvolysis,
Supporting Information. Additional discussion, experi-
mental procedures, kinetic data and simulations, substrate
and product characterization data and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
protodesilylation, or oxidation under the arylation
conditions; see the SI for details. Hindered arenes
underwent slow (o-3ah) or no reaction (o-3ai). When two
silyl groups are present in the substrate (o-1ac), coupling
is selective for the more-reactive ortho-silyl group,
yielding o-3ac; the meta-arylated isomer could not be
ACKNOWLEDGMENT
18
detected.
We thank AstraZeneca and CatSci for support.
Conclusions
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Table of Contents Graphic
R
slow
krel = 1
R = Me
L
X
X
Au
Au
R
Br
S
Br
H
S
X
X
krel = 190
R = OMe
R
fast
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