Room-Temperature Gold-Catalysed Arylation of Heteroarenes: Complementarity to Palladium Catalysis

Article abstract of DOI:10.1002/chem.201602893

Tailoring of the pre-catalyst, the oxidant and the arylsilane enables the first room-temperature, gold-catalysed, innate C?H arylation of heteroarenes. Regioselectivity is consistently high and, in some cases, distinct from that reported with palladium ca

Full text of DOI:10.1002/chem.201602893

A Journal of
Accepted Article
Title: Room Temperature Gold-Catalysed Arylation of Heteroarenes: Complementa-
rity to Palladium Catalysis
Authors: Guy Charles Lloyd-Jones; Alexander Cresswell
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Chemistry - A European Journal
10.1002/chem.201602893
COMMUNICATION
Room Temperature Gold-Catalysed Arylation of Heteroarenes:
Complementarity to Palladium Catalysis
Alexander J. Cresswell[a] and Guy C. Lloyd-Jones*[a]
Abstract: Tailoring of the pre-catalyst, the oxidant and the arylsilane
enables the first room temperature, gold-catalysed, innate C–H
arylation of heteroarenes. Regioselectivity is consistently high and,
in some cases, distinct from that reported with palladium catalysis.
Tolerance to halides and boronic esters, in both the heteroarene and
silane partners, provides orthogonality to Suzuki-Miyaura coupling.
more rapidly-activating pre-catalyst2 improved conversion (40%
of 4), but interaction of 1 with the in situ iodine(III) oxidant1
remained a problem. However, by sterically-encumbering the
oxidant (3b-c), the undesired oxidation was reduced, and 4
could be obtained in 87% yield over 2.5 hours using oxidant 3c.7
Because the methanol co-solvent1 is known to be a catalyst
inhibitor,2 we tested whether the arylation of 1 could be
accelerated using methanol-free conditions. However, despite a
faster initial rate, the generation of 4 ceased after approximately
35% conversion of 2,8 with unreacted indole 1 then being slowly
consumed in a non-productive oxidation (Figure 1, left-hand plot).
Having found that removal of the methanol causes reaction
stalling, we tested whether a silyl-tethered alcohol could act as a
methanol surrogate.8 Accordingly, replacing aryl-TMS 2 with
arylsilane 5, bearing a 3-hydroxypropyldimethylsilyl (HPDMS)
group,9 resulted in much more efficient arylation (>90%
conversion of 5 in under an hour, Figure 1 right-hand plot)
allowing isolation of 4 in 87% yield. Notably, the addition of one
equivalent of methanol to 2 is not an effective substitute for 5:
the generation of 4 ceases after 40% conversion of 2 (see SI).
We recently reported a new route to biaryls via oxidative
cross-coupling of moderately electron-rich arenes with
aryltrimethylsilanes.1,2 This gold-catalysed reaction exploits the
innate SEAr-type reactivity of the arene partner, rather than a
directing group, and proceeds under mild and convenient
conditions (Scheme 1).
Ph3PAuOTs (1- 2 mol%)
R2
R2
R1
+
PhI(OAc)2, CSA
50:1 CHCl3:MeOH
room temperature
Me3Si
(1.0 equiv)
R1
(1.0 equiv)
Scheme 1. Gold-catalysed C–H arylation.1,2 CSA = camphorsulfonic acid.
F
Au pre-catalyst (2 mol%)
arylsilane 2 or 5 (1.0 equiv)
F
F
However, although many substituents are tolerated,
including esters, aldehydes, alcohols, and (pseudo)halides, the
only heteroarenes we were able to efficiently arylate under our
original conditions were 2-bromothiophenes.1,2 By stabilising the
Au(III)2 catalyst with a strongly electron donating 2-pyridylidene
ligand, Itami and Segawa et al. showed that arylation of other
heteroarenes was feasible.3 However, the range was still limited
(four isoxazoles, one indole, and one benzothiophene) the yields
moderate (13–54%), and the reaction rather slow (5 mol% Au,
65 °C, 18-48h).3 Larrosa et al. have also reported a gold-
catalysed polyfluoroarylation of π-rich heteroarenes via double
C–H activation (5 mol% Au, 35 mol% Ag, 110 °C).4
The area of metal-catalysed, innate C–H arylation of
heteroarenes5,6 remains dominated by palladium catalysis, with
a frequent requirement for highly elevated temperatures (often
>100 °C), an excess of one coupling partner, stoichiometric Ag
or Cs additives, or inert conditions. In this respect, we were
motivated to explore the potential of our gold-catalysed arylation
methodology1 to address these issues, and perhaps even
enable C–H arylations which are not currently possible with
palladium.
oxidant 3 (1.3 equiv)
CSA (1.5 equiv)
CDCl3, 22 °C
N
N
1
4
Ts
Ts
AcO
R
I
OAc
Me Me
SiMe3
F
R
Si
OH
3a, R = H
3b, R = Me
3c, R = i-Pr
F
5
2
R
pre-catalyst oxidant
entry
time (h)
4
MeOH
ArSiR3
1
2
3
4
5
6
Ph3PAuOTs
thtAuBr3
thtAuBr3
thtAuBr3
thtAuBr3
thtAuBr3
3a
3a
3b
3c
3c
3c
2
2
2
2
2
5
2%
2%
2.3a
1.5a
2.0a
2.7a
0.3b
1.0b
16%
40%
62%
87%
29%
87%
2%
2%
none
none
for entry 5
(Ar-TMS 2)
for entry 5
0.11#
0.11#
(Ar-HPDMS 5)
0.10#
0.09#
0.08#
0.07#
0.06#
0.05#
0.04#
0.03#
0.02#
0.01#
0.00#
0.10#
0.09#
0.08#
0.07#
0.06#
0.05#
0.04#
0.03#
0.02#
0.01#
0.00#
4
2
1
Initial investigations focused on the arylation of indole 1
with Ar-TMS 2 to give 4 (Figure 1). Using our originally-reported
conditions,1 arylated indole 4 was produced in only 16% yield,
with the remainder of the indole 1 being consumed by competing
(uncatalysed) oxidative decomposition. Using thtAuBr3 as a
4
1 + 5
60# 90#
0#
30#
0#
30#
60#
90#
time / min
time / min
[a]
Prof. Dr G. C. Lloyd-Jones and Dr A. J. Cresswell
EaStCHEM, School of Chemistry
Figure 1. Identification of conditions for efficient C–H arylation of indole 1. All
yields are calculated by 19F NMR against an internal standard. aTime at which
1 is fully consumed. bTime at which arylation ceases. Ar = 4-fluorophenyl;
CSA = camphorsulfonic acid; tht = tetrahydrothiophene; Ts = 4-toluenesulfonyl.
University of Edinburgh
Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ, U.K.
E-mail: Guy.Lloyd-Jones@ed.ac.uk
Supporting information for this article is given via a link at the end of
the document.

Chemistry - A European Journal
10.1002/chem.201602893
COMMUNICATION
Having established a rapid and efficient arylation process,
concise routes for Ar-HPDMS synthesis were next designed.
Reagents 7 and 8, easily prepared via alkene hydrosilylation in
one or two steps without chromatography (see SI), can be
conveniently applied in one-pot processes (Scheme 2). For
example, ‘HPDMS chloride’ 7 adds to the aryllithium derived
from 9 to afford Ar-HPDMS 10 after O-desilylation, and adapting
the trialkylsilylation procedure of Yamanoi and Nishihara,10
‘HPDMS hydride’ 8 silylates iodoarene 11 to give Ar-HPDMS 12
after cleavage of the THP protecting group. Although the latter
Me Me
Si
Me Me
OTMS
Si
OTHP
Cl
H
7 ('HPDMS chloride')
8 ('HPDMS hydride')
i) BuLi (1.05 equiv)
Lithiation
7 (1.2 equiv), THF
- 78 °C to rt
Me Me
Br
Si
OH
OH
ii) K2CO3, MeOH, rt
Br
Br
10, 82%
9
Rh-Catalysis
procedure
suffers
from
competing
reduction
RhCl(CO)(PPh3)2 (5 mol%)
8 (3.0 equiv)
(protodeiodination)10 this method does tolerate functionality that
would otherwise be incompatible with lithiation-silylation
approaches (e.g. -CO2Me). With convenient routes to Ar-
HPDMS reagents in hand, their performance in heteroarene C–
H arylations was evaluated next.
Me Me
Si
MeO2C
I
K3PO4 (3.0 equiv)
MeO2C
NMP, rt
then TsOH, MeOH, rt
12, 51%
11
Scheme 2. Ar-HPDMS preparation. HPDMS = 3-hydroxypropyldimethylsilyl;
NMP = N-methylpyrrolidinone; TMS = trimethylsilyl; THP = tetrahydropyranyl;
Ts = 4-toluenesulfonyl.
Me Me
Si
R
F
OH
R
F
(1.0 equiv)
N
Ts
1 (1.0 equiv)
thtAuBr3 (2 mol%)
3c (1.3 equiv), CSA (1.5 equiv)
CHCl3, 22 °C
N
Ts 14
HPDMS arylsilane
Me Me
Time
1.5 h
Product
F
Yield
HPDMS arylsilane
Time
2 h
Product
Yield
89%
CF3
F
F
Me Me
Si
OH
Si
OH
87%
13g
5
F3C
14g
4
F
N
Ts N
F
Ts
F
F
Me Me
Si
Me Me
Si
OH
OH
OH
1 h
89%
5 h
80%
0%
13h
13a
14a
14b
F
14h
Ts N
Ts N
F
F
F
F
Me Me
Si
Me
Me Me
Si
OH
-
-
43%a
69%
14 h
13i
13j
14i
13b
13c
F
F
Me
N
Ts
N
Ts
CF3
Me Me
F
Me
Br
F
F3C
Si
OH
Me Me
Si
OH
0%
0.5 h
CF3
Me
CF3
14c
14j
N
Ts
N
Ts
SiMe3
F
Me Me
Si
F
Me Me
Si
OH
OH
1.5 h
65%
67%
2 h
85%
13k
10
Me3Si
Me3Si
14k
14l
N
Ts
Br
14d
N
Ts
F
Me Me
Si
OPiv
F
Me Me
Si
OH
2 h
OH
SiMe3
2 h
1 h
80%
13l
13e
N
Ts
PivO
O
B
14e
N
Ts
Me Me
Si
F
F
O
OH
1.5 h
Me Me
Si
MeO2C
OH
73%b
13m
73%
O
CO2Me
B
12
14m
O
14f
N
Ts
Ts N
Scheme 3. Isolated yields from arylation of indole 1 followed by 19F NMR at 22 °C. tht = tetrahydrothiophene; Piv = pivaloyl; Ts = 4-toluenesulfonyl. aStalled at
65% conversion of 13b. bStalled at 75% conversion of 13f

Chemistry - A European Journal
10.1002/chem.201602893
COMMUNICATION
With respect to the arylsilane (Scheme 3), the process is
compatible with a range of useful spectator functionalities,
including carboxyl (14f), boryl (14m), silyl (TMS) (14k,l) and
halogen (Br) groups (14d). Paralleling earlier work with Ar-TMS
reagents (e.g. 2) for C–H arylation,1,2,3 Ar-HPDMS 13b bearing
substituents proved unreactive. The generality of the C–H
arylation protocol with respect to the heteroarene partner is also
good (Scheme 4), with regioselectivity essentially quantitative
(>95%) in all but one case (i.e. 16r, ≥80%). Again, the reaction
tolerates a range of functionalities on this partner, including
ortho-substitution led to slow and inefficient arylation (43% yield), carboxyl (16b-d,l-n), boryl (16k), and halogen (Br, Cl) groups
whereas silanes 13i-j bearing highly electron-withdrawing
(16a,d,f-i,l,o-q).
Me Me
Si
OH
F
5 (1.0 equiv)
F
Het
Het
thtAuBr3 (2 mol%)
conditions A or B
CHCl3, 22 °C
15 (1.0 equiv)
16
Heteroarene
Conditions
Time
Product
Yield
Heteroarene
Conditions
A
Time
1 h
Product
Yield
56%
O
B
O
O
F
Br
N
Br
16a Ts
EtO2C
N
O
B
F
15a Ts
1 h
10 h
9 h
53%b
45%
72%
A
EtO2C
N
Ts
N
16k
A
A
A
3 h
62%
15k
Me
N
Me
16b Ts
MeO2C
Ts
N
F
MeO2C
Br
15b Ts
MeO2C
B
B
MeO2C
O
Br
O
F
1.5 h
60%a
64%
15l
16l
Me
F
O
Me
O
15c
F
16c
MeO2C
N
MeO2C
MeO2C
MeO2C
MeO2C
Ts
Cl
15m
16m
Cl
N
Ts
5 h
O
O
F
15d
16d
57%c
74%
F
B
B
3 h
2 h
O
MeO2C
15n
O
F
16n
A
A
0.5 h
1.5 h
85%
86%
N
Br
Br
Br
N
Ts
15e
15f
16e
Ts
F
Br
S
Br
Br
S
F
F
15o
16o
Br
Br
Br
N
N
B
B
2 h
76%
71%
Ts
16f
Ts
Br
S
Br
F
S
Br
Br
15p
16p
A
A
A
2.5 h
1.5 h
1.5 h
82%
89%
76%
Br
N
N
17 min
Ts
15g
15h
16g
Ts
S
S
F
F
15q
16q
Br
Br
F
5
5
N
3
16h
N
Ts
3
Ts
46%d
78%e
67%e
A
A
A
10 min
1.7 h
33 h
Me
S
F
S
Me
15r
16r
F
F
O
O
N
Ts
Br
Br
N
Ts
MeN
O
MeN
O
15i
16i
15s
15t
16s
N
N
Me
F
MeO
Me
MeO
A
12 min
80%
N
N
16j
O
N
Ts
15j
Me
Ts
16t
O
N
Me
Scheme 4. Isolated yields from room temperature arylation of 15a-t. followed by 19F NMR at 22 °C. Conditions: A = 3c (1.3 equiv) + CSA (1.5 equiv); B =
PhI(OH)OTs (1.3 equiv). Ar = 4-fluorophenyl; pin = pinacolato; Ts = 4-toluenesulfonyl. aContaminated with 8% diarylated product. bStalled at 72% conversion of
15k. c5.0 equiv of 15n. d88:12 C(3):C(5). e4 mol% of thtAuBr3

Chemistry - A European Journal
10.1002/chem.201602893
COMMUNICATION
In most cases we employed the sterically-encumbered
oxidant 3c (conditions A) developed for the arylation of indole 1,
but for slower-reacting 15l-q, commercially-available Koser’s
reagent [PhI(OH)OTs] proved superior (conditions B), leading to
increased arylation rates.11 Some heteroarenes (including
isoaxazole, for which the Itami-Segawa catalyst3 is successful)
proved unsuitable, either due to a lack of reactivity, or because
they gave complex mixtures of products (see SI for full details)
It is particularly instructive to compare and constrast our
new methodology with prior art in metal-catalysed, innate C–H
arylation of heteroarenes. For example, indoles 4,15f-k have not
previously been used in C–H arylation, and the only other “low”
temperature (<100 °C) methods for the β-arylation of indoles (as
opposed to α-arylation)12 include a Cu-catalysed protocol with
diaryliodonium salts (35 °C)13 and an oxidative, Pd-catalysed
process with arylboronic acids (80 °C).6c The successful
α-arylation of brominated pyrrole 15a and furan 15l are also
significant, as there are no other publsihed examples of C–H
arylation of these or other ring-halogenated pyrroles/furans. The
regioselective arylation of brominated thiophenes 15o-p14 and
benzo[b]thiophenes 15q15 and 15r under such mild conditions is
also likely to find application in the preparation of functional
organic materials.16,17
the heteroarene), elevated temperatures (80–160 °C), and,
almost invariably, an inert atmosphere. By constrast, all of these
heteroarenes can be arylated at ambient temperature, under air,
in ≤3 hours under our gold-catalysed conditions, typically
employing 2 mol% Au and 1:1 coupling partner stoichiometry.
Complementarity to Pd catalysis is also apparent for the
selective23 arylation of pyrrole 15m, which contrasts with the
-arylation of 15m reported with Pd(TFA)2 as the catalyst
(Scheme 5, left).24 Similarly, the β-arylation of pyridone 15t is the
first example of C–H arylation25 at this position that does not
require polyfluorinated arene partners (Scheme 5, right).26
Ar(F)n
MeO2C
Ph
N
O
N
Ts
Me
65%
62- 86%
C(5)-polyfluoro-
arylation
C(4)-selective
ArF-H (3.0 equiv)
Pd(OAc)2 (10 mol%)
Ag2CO3, Si-Pr2
Ph-H (33 equiv)
Pd(TFA)2 (10 mol%)
AgOAc, PivOH
80 °C
[ref. 24]
[ref. 26]
dioxane, 130 °C
MeO2C
N
15m
O
N
15t
Ts
Me
C(3)-selective
C(5)-arylation
this work
(Au cat. 22 °C)
this work
(Au cat. 22 °C)
Heteroarene
(and arylation site)
Examples Ar-H:Ar-X
Pd
Ag or Cs
Temp Inert?
Ar
& Yields
Ratio
Loading Additives
Ar
MeO2C
MeO2C
N
[>10
publications]
O
N
2 : 1
argon
argon
0.01- 1 mol%
0.5- 1 mol%
-
-
150 °C
130 °C
15c
Ts
16m, 72%
Me
Me
O
16t, 67%
13 examples
(58- 78%
wrt Ar-X)
4 : 1
MeO2C
O
Scheme 5. Complementarity to Pd catalysis: β-arylations of pyrrole 15m and
pyridone 15t. Ar = 4-fluorophenyl; ArF = perfluoroaryl; TFA = trifluoroacetate;
Piv = pivaloyl; Ts = 4-toluenesulfonyl.
15n
Br
5 examples
(67- 87%
wrt Ar-X)
15o
AgNO3
AgNO3
1.2 : 1
1.2 : 1
5 mol%
5 mol%
argon
argon
100 °C
100 °C
Br
S
Br
In summary, we have developed the first room
temperature, gold-catalysed, innate C–H arylation of
heteroarenes, proceeding with high chemo- and regioselectivity.
The process is facilitated by use of a rapidly activating thtAuBr3
pre-catalyst,2 the exclusion of methanol as co-solvent, and the
use of tailored oxidants and arylsilane partners.
Complementarity to Pd catalysis is apparent not only from
the exceptionally mild and non-inert reaction conditions, but also
the ability to effect certain arylations which are currently not
possible with Pd catalysts. Moreover, as far as we are aware,
this work provides the first examples of boryl spectator
functionality (pinB) in both coupling partners in a metal-catalysed
C–H arylation (i.e. 14m and 16k).27 Together with halides 14d
and 16a,d,f-i,l,o-q, these products highlight the orthogonality of
gold-catalysed C–H arylation to Suzuki-Miyaura cross-coupling.
1 example
(65%
wrt Ar-X)
15p
Br
S
Br
24 examples
(8- 88%
wrt Ar-X)
1.5 : 1
1 : 2
0.5 mol%
9.4 mol%
-
argon
air
80 °C
15q
S
1 example
(16%)
Cs2CO3
150 °C
15r
Me
S
O
6 examples
(42- 80%
+ 7- 20%
a -isomer)
MeN
O
15s
1 : 2
5 mol%
Cs2CO3
argon
160 °C
N
Me
Table 1. State-of-the-art in Pd-catalysed C–H arylation of selected
heteroarenes with aryl halides (see main text for references).
As a further illustration of practical advance, the state-of-
the-art in Pd-catalysed C–H arylation of some of the
heteroarenes employed in the current work are presente din
Table 1 (i.e. for 15c,18 15n,19 15o,p,14 15q,16 15r,20 and 15s21).22
Although catalyst loadings in some cases are <1 mol%, all of the
procedures require an excess of one coupling partner (typically
Experimental Section
Preparation of 14a. A 30 mL vial equipped with a stirrer bar was charged
with 13a (194 mg, 1.00 mmol, 1.0 equiv), 1 (289 mg, 1.00 mmol, 1.0
equiv), thtAuBr3 (10.5 mg, 0.02 mol, 2 mol%), and CHCl3 (10 mL). The
mixture was stirred for ca. 1 min to fully dissolve the thtAuBr3 pre-catalyst,

Chemistry - A European Journal
10.1002/chem.201602893
COMMUNICATION
resulting in a deep red-orange solution. Taking no precautions to exclude
air or moisture, 3c (583 mg, 1.30 mmol, 1.3 equiv) and CSA (356 mg,
1.50 mmol, 1.5 equiv) were added simultaneously in a single portion, and
the vial sealed with a screw cap. Over approximately 1 min, the solution
changed to a clear pale-yellow solution, signifying pre-catalyst activation.
After 1 h, 19F NMR indicated no further reaction and Celite (ca. 4 g) was
added. The volatiles were allowed to evaporate to give a free-flowing
powder. Purification via flash column chromatography (100 g SiO2, 40
mm Ø, 60:40 hexane/toluene, ca. 14 mL fractions) gave 14a as a clear,
colorless gum (332 mg, 89%).
[13] R. J. Phipps, N. P. Grimster, M. J. Gaunt, J. Am. Chem. Soc. 2008, 130,
8172–8174.
[14] K. Kobayashi, A. Sugie, M. Takahashi, K. Masui, A. Mori, Org. Lett.
2005, 7, 5083–5085.
[15] For
a
chemoselective, ligand-free, Pd-catalysed α-arylation of
3-bromobenzo[b]thiophene 15q to give 16q, see: I. Smari, H. B. Ammar,
B. B. Hassine, J.-F. Soulé, H. Doucet, Synthesis 2015, 47, 3354–3362.
[16] For reviews on the synthesis of functional organic materials via C–H
functionalisation see: a) Y. Kuninobu, S. Suekia, Synthesis 2015, 47,
3823–3845; b) Y. Segawa, T. Maekawa, K. Itami, Angew. Chem. Int.
Ed. 2015, 54, 66–81.
[17] For
a
recent room temperature, Heck-like β-arylation of
benzo[b]thiophenes with Ar-I, see: olletto, S slam, uli -
Hern nde , arrosa, J. Am. Chem. Soc. 2016, 138, 1677−1683
[18] For the seminal report, see: A. Battace, M. Lemhadri, T. Zair, H. Doucet,
M. Santelli, Organometallics 2007, 26, 472–474.
Acknowledgements
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].
[19] H. Y. Fu, H. Doucet, Eur. J. Org. Chem. 2011, 7163–7173.
[20] D.-T. D. Tang, K. D. Collins, F. Glorius, J. Am. Chem. Soc. 2013, 135,
7450−7453
[21] a) K. H. Kim, H. S. Lee, J. N. Kim, Tetrahedron Lett. 2011, 52, 6228–
6233; b) M Čerňov , Čerňa, R Pohl, M Hocek, J. Org. Chem. 2011,
76, 5309–5319; c) M Čerňov , R Pohl, M Hocek, Eur. J. Org. Chem.
2009, 3698–3701.
Keywords: gold catalysis • C–H functionalisation • arylation •
heteroarenes • silicon
[22] Where several publications are on record, the conditions given in Table
1 represent the most practical or inexpensive method to date (i.e.
lowest Pd loading, best Ar-H:Ar-X stoichiometry, etc.). Aside from the
arylation of 15q, all of the methods surveyed required temperatures
≥100 °
[1]
[2]
[3]
[4]
[5]
L. T. Ball, G. C. Lloyd-Jones, C. A. Russell, Science 2012, 337, 1644–
1648.
L. T. Ball, G. C. Lloyd-Jones, C. A. Russell, J. Am. Chem. Soc. 2014,
136, 254–264.
[23] For Rh-catalysed β-arylation of other pyrroles with Ar-I at 150 °C, see:
K. Ueda, K. Amaike, R. M. Maceiczyk, K. Itami, J. Yamaguchi, J. Am.
Chem. Soc. 2014, 136, 13226−13232
K. Hata, H. Ito, Y. Segawa, K. Itami, Beilstein J. Org. Chem. 2015, 11,
2737–2746.
X. C. Cambeiro, N. Ahlsten, I. Larrosa, J. Am. Chem. Soc. 2015, 137,
15636–15639.
[24] J. K. Laha, R. A. Bhimpuria, D. V. Prajapati, N. Dayal, S. Sharma,
Chem. Commun. 2016, 52, 4329–4332.
For recent reviews on metal-catalysed C–H arylation of heteroarenes
see: a) R. Rossi, M. Lessi, C. Manzini, G. Marianetti, F. Bellina,
Tetrahedron 2016, 72, 1795–1837; b) R. Rossi, F. Bellina, M. Lessi, C.
Manzini, L. A. Perego, Synthesis 2014, 46, 2833–2883.
For selected studies on C–H arylation featuring diverse heteroarene
substrates see: a) A. Skhiri, A. Beladhria, K. Yuan, J.-F. Soulé, R. B.
Salem, H. Doucet, Eur. J. Org. Chem. 2015, 4428–4436; b) Y. Huang,
D. Wu, J. Huang, Q. Guo, J. Li, J. You, Angew. Chem. Int. Ed. 2014, 53,
12158–12162; c) K. Yamaguchi, H. Kondo, J. Yamaguchi, K. Itami,
Chem. Sci. 2013, 4, 3753–3757; d) D. P. Hari, P. Schroll, B. König, J.
Am. Chem. Soc. 2012, 134, 2958–2961; e) B. Liégault, D. Lapointe, L.
Caron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009, 74, 1826–1834.
Oxidant 3c can be prepared on decagram scale in two steps from
inexpensive 1,3,5-triisopropylbenzene. The corresponding iodoarene
can be recovered (≥95%, column chromatography) after gold-catalysed
arylation and recycled.
[25] For gold-catalysed, C(5)-selective C–H alkynylation of 2-pyridones, at
80 °C, see: Y. Li, F. Xie, X. Li, J. Org. Chem. 2016, 81, 715–722.
[26] Y. Chen, F. Wang, A. Jiab, X. Li, Chem. Sci. 2012, 3, 3231–3236.
[27] For a recent example of spectator pinacolatoboryl (Bpin) functionality
on the Ar–H partner in a Pd-catalysed direct arylation process, see ref.
[17].
[6]
[7]
[8]
Methanol (directly or indirectly) intercepts the silicenium ion (Me3Si+)
that formally develops during SEAr-type auration of an arylsilane - see
references [1] and [2]. The origin of reaction stalling in the methanol-
free coupling of
investigations.
1 with 2 is the subject of ongoing mechanistic
[9]
There is one prior application of an aryl-(3-hydroxypropyl)dimethylsilane,
in a Cu-catalysed allyl-coupling, see: A. Tsubouchi, D. Muramatsu, T.
Takeda, Angew. Chem. Int. Ed. 2013, 52, 12719–12722.
[10] A 66:34 ratio of silylation:reduction is observed with 11; analogous
reductions occur in the Yamanoi-Nishihara procedure: a) Y. Yamanoi,
H. Nishihara, J. Synth. Org. Chem. Jpn. 2009, 67, 778–786; b) Y.
Yamanoi, H. Nishihara, J. Org. Chem. 2008, 73, 6671–6678.
[11] Koser's reagent [PhI(OH)OTs] is not compatible with the more reactive
(electron-rich) heteroarenes. These require use of 3c + CSA.
[12]
For reviews on indole C–H arylation methods see: a) A. H. Sandtorv,
Adv. Synth. Catal. 2015, 357, 2403–2435; b) N. Lebrasseur, I. Larrosa
in Advances in Heterocyclic Chemistry, Vol. 105 (Ed.: A. Katritzky),
Academic Press, USA, 2012, pp. 309–351.

Chemistry - A European Journal
10.1002/chem.201602893
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Gold-catalysed, room temperature,
C–H arylation of heteroarenes
provides a mild and practical synthetic
protocol compatible with a range of
functional groups, including boronic
esters and halides
Alexander J. Cresswell and
Guy C. Lloyd-Jones*
Me Me
Si
OH
R
(1.0 equiv)
R
Page No. – Page No.
thtAuBr3 (2 mol%)
Het
R'
Het
R'
iodine(III) oxidant
CHCl3, 22 °C
32 examples
Room Temperature Gold-Catalysed
Arylation of Heteroarenes:
Complementarity to Palladium
Catalysis
n
n
n
n
average yield 71%
n
n
n
n
furans
typically >95% regioselectivity
tolerant of: Cl, Br, Bpin,TMS
typically complete in <2 h
pyrroles & indoles
(benzo)thiophenes
2H-pyridone & uracil