Ag(I)-C-H Activation Enables Near-Room-Temperature Direct α-Arylation of Benzo[ b]thiophenes

Article abstract of DOI:10.1021/jacs.8b05361

The first example of near-room-temperature α-arylation of benzo[b]thiophenes is reported. The discovery rests on the observation of a switch in α-/β-regioselectivity at different loadings of Pd₂(dba)₃·CHCl₃ in the coupling between benzo[b]thiophene and 4-iodotoluene. We show that this unprecedented regioselectivity switch is driven by a Ag(I)-mediated C-H activation at the α-C-H position, which becomes the dominant mode of reactivity at low concentrations of Pd. Competition experiments, kinetic studies, KIE, and D/H scrambling experiments have been carried out supporting this mechanism.

Full text of DOI:10.1021/jacs.8b05361

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Article
Ag(I)-C–H Activation Enables Near-Room
Temperature Direct #-Arylation of Benzo[b]thiophenes
Chiara Colletto, Adyasha Panigrahi, Jaime Fernandez-Casado, and Igor Larrosa
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05361 • Publication Date (Web): 09 Jul 2018
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Ag(I)-C–H Activation Enables Near-Room Temperature Direct α-
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Arylation of Benzo[b]thiophenes
Chiara Colletto,‡ Adyasha Panigrahi,‡ Jaime FernándezꢀCasado, and Igor Larrosa*
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School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, U.K.
Supporting Information Placeholder
ABSTRACT: The first example of near room temperature αꢀarylation of benzo[b]thiophenes is reported. The discovery rests on the
.
observation of a switch in αꢀ/βꢀ regioselectivity at different loadings of Pd2(dba)3 CHCl3 in the coupling between benzo[b]thiophene
and 4ꢀiodotoluene. We show that this unprecedented regioselectivity switch is driven by a Ag(I)ꢀmediated C–H activation at the αꢀ
C–H position, which becomes the dominant mode of reactivity at low concentrations of Pd. Competition experiments, kinetic studꢀ
ies, KIE and D/H scrambling experiments have been carried out supporting this mechanism.
1. INTRODUCTION
tivity of a C–H functionalisation process has been shown to
originate in a change in catalyst concentration. Driven by the
potential mechanistic implications and the possibility to deꢀ
velop unprecedentedly mild conditions for C2ꢀarylation, we
proceeded to investigate the origin of this regioselectivity
switch. Given that changes in catalyst concentration should
not affect the ratios of the different inꢀcycle catalytic species
in a typical catalytic cycle (Scheme 3, Path A),10 we hypotheꢀ
sized that this switch could originate in the existence of an
alternative pathway involving a coꢀcatalyzed process.
The widespread presence of arylated benzo[b]thiophenes
and thiophenes in biological compounds, pharmaceuticals and
material sciences makes these scaffolds attractive targets for
synthetic methodologies (Scheme 1).1 While conventional
crossꢀcouplings are still widely used,2 direct C–H arylation has
emerged over the last two decades as a powerful approach that
eliminates the need for prefunctionalisation, thus leading to
shorter synthetic routes. The direct C2ꢀarylation of benꢀ
zo[b]thiophene was first demonstrated by Ohta in 1990,3 and
over the last decade several further examples have been reꢀ
ported using Pd,4 Cu5 or Ir6 as catalysts.7 However, all the
methodologies reported require the use of elevated temperaꢀ
tures (100ꢀ150 °C), which limits their functional group comꢀ
patibility. Furthermore, high catalyst loadings are typically
required with few exceptions.4g,i,j,m The development of mild
conditions for the C2ꢀarylation of benzo[b]thiophenes is thereꢀ
fore a highly desirable synthetic target, which would allow a
significant expansion of the functional group tolerance and
applicability of the methodology. Herein we report studies
leading to the discovery of a novel Ag(I)ꢀC–H activationꢀ
based methodology that overcomes the aforementioned limitaꢀ
tions, and affords the first nearꢀroom temperature C2ꢀarylation
of benzo[b]thiophenes.8 This new methodology offers wide
functional group tolerance, operates at nearꢀroom temperature
and requires only 0.4 mol % Pdꢀcatalyst loading.
Scheme 1. Examples of 2ꢀarylbenzo[b]thiophenes
Scheme 2. Dependence on the catalyst loadings of the regiꢀ
oselectivity of coupling between 1a and 2aa,b
Our investigation began with an unexpected observation
during the development of our recently reported C3ꢀselective
C–H arylation of benzo[b]thiophenes (1a) with aryl iodides
(2a, Scheme 2).9 During optimization of the Pdꢀcatalyst loadꢀ
ing of this process we observed that the ratio C2/C3 showed a
marked dependence on the concentration of Pd-catalyst used
in the experiment (Scheme 2). Indeed, while 1:>99 selectivity
a Yield determined by 1HꢀNMR using 1,3,5ꢀtrimethoxybenzene as internal
standard. 1a (0.5 mmol), 2a (0.75 mmol), Ag2CO3 (0.375 mmol), HFIP
(0.5 mL).
b
Through a combination of stoichiometric and kinetic studies,
we have recently demonstrated that Ag(I)ꢀsalts are able to
carry out C–H activation of electronꢀdeficient arenes.11 This
allows for a C–H arylation process that occurs with very low
catalyst loadings of Pd (Scheme 4a). Concurrently, Sanford
.
was obtained when using 2.5 mol % Pd2dba3 CHCl3, this ratio
was eroded when decreasing the catalyst loading, and eventuꢀ
ally reversed at loadings as low as 0.05 mol %. To the best of
our knowledge this is the first time a change in the regioselecꢀ
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and coꢀworkers established the same prominent role of Ag(I)ꢀ
ence of Ag2O (Table 1, entry 3), increasing to 34% when
NaOAc was added as an additive.14
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salts on the C–H activation of both polyfluoroarenes and thioꢀ
phenes at 100 °C (Scheme 4b).12 Additionally, the investigaꢀ
tion of a selective allylation of aryl C–H bonds catalyzed by
Pd and mediated by AgOPiv led Hartwig and coꢀworkers to
the isolation of the first phosphineꢀligated arylsilver(I) comꢀ
plex, which was shown to react with an allyl–Pd complex
(Scheme 4c).13
Encouraged by these results we then explored the develꢀ
opment of a low temperature C2ꢀarylation protocol based on
the observed Ag(I)ꢀC–H activation. Remarkably, reaction of
1a with 2a proceeded at nearꢀroom temperature in 45% yield
when carried out in the presence of 0.75 equiv of Ag2O and
0.5 equiv of NaOAc, and only 0.2 mol % Pd2dba3·CHCl3
(Table 2,entry 2). A switch of catalyst to 0.4 mol % Pd(OAc)2
further increased the yield of product 3aa to 54% (Table 2,
entry 3). Inverting the stoichiometry of the two coupling partꢀ
ners increased the yield to 73% (Table 2, entry 4), consistently
with the proposed rate limiting C–H activation. Finally, inꢀ
creasing the amount of Ag2O to 1 equiv afforded 3aa in 83%
yield (Table 2, entry 5).15,16
Scheme 3. Proposed mechanism for formation of 4 (path
A) and 3 (path B)
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Table 1. D/H scrambling studies to test for Ag(I)ꢀC–H
activationa
Scheme 4. Previous methodologies reporting experimental
evidence of Ag(I)ꢀmediated C–H activation
a Ratio determined by quantitative 1HꢀNMR. b NaOAc (0.5 equiv).
Table 2. Optimization of reaction conditionsa,b
Entry [Pd]
Additive
3aa (%)
4aa (%)a
.
1
ꢀ
26
10
Pd2(dba)3 CHCl3
.
2
NaOAc
NaOAc
NaOAc
NaOAc
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54
73
83
1
6
5
3
Pd2(dba)3 CHCl3
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
4c
5c,d
a Yield determined by 1HꢀNMR using 1,3,5ꢀtrimethoxybenzene as internal
b
c
standard. 1a (0.25 mmol). 1a (2 equiv), 2a (1 equiv, 0.25 mmol).
d Ag2O (1 equiv).
Based on these precedents, we proposed that a Ag(I)ꢀmediated
C2ꢀselective C–H activation process could be responsible for
the observed regioselectivity switch on the arylation of benꢀ
zo[b]thiophene, via competitive Path B (Scheme 3). If the
Ag(I)ꢀmediated C–H activation is the rate determining step of
the process leading to C2ꢀarylation, then a lowering of Pd
catalyst loading could lead to the observed switch by disproꢀ
portionately slowing down the C3ꢀarylation process.
With the optimized conditions in hand, we proceeded to invesꢀ
tigate the scope of the reaction (Table 3). Iodoarenes bearing
either electronꢀdonating (2aꢀ2d) or electronꢀwithdrawing
groups (2eꢀ2o) in paraꢀposition reacted in good to excellent
yields. Remarkably, the mild reaction conditions enabled
compatibility with alcohol (3ad), aldehyde (3ae) and ketone
(3af) substituents, which often suffer from issues of chemoseꢀ
lectivity when harsher conditions are employed. Halogen
substituents were also tolerated giving the possibility to further
functionalize the products through traditional crossꢀcoupling
(3ahꢀ3aj).2 Highly electronꢀpoor iodoarenes showed modest
reactivity, although higher yields can be obtained by increasꢀ
ing the temperature to 50 °C (3akꢀ3al). While 4ꢀiodoaniline
was incompatible with the system, probably due to inhibiting
coordination of the lone pair of the nitrogen (2m) to the cataꢀ
lyst,17 amide and cyano substituted iodoarenes reacted
2. RESULTS AND DISCUSSION
2.1. Reaction Optimization and Scope
Inspired by this mechanistic hypothesis, we decided to probe
whether a low temperature Ag(I)ꢀmediated C2ꢀselective C–H
activation would be feasible. We studied the D/H scrambling
of 2ꢀdꢀbenzo[b]thiophene (d1ꢀ1a) in the presence of different
silver additives in hexafluoroꢀ2ꢀpropanol (HFIP) (Table 1).
Gratifyingly, 10% D/H scrambling was observed in the presꢀ
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yield without observing racemization at the chiral centre.19
Table 3. Direct C–H Arylation of Unsubstituted
Benzo[b]thiophene 1a with Iodoarenes 2aꢀaꞌa
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2
3
4
Finally, the reaction is amenable to scaling up: the arylation of
1a with 2a was performed on a 20 mmol scale, obtaining the
desired arylated product in 71% yield and 97:3 (C2:C3)
regioselectivity.
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The reactivity of substituted benzo[b]thiophenes was then
tested with 4ꢀiodotoluene 2a as the coupling partner (Table 4).
In general, 4 and 5ꢀsubstituted benzo[b]thiophenes afforded
high yields and regioselectivities of the corresponding αꢀ
arylated products (3baꢀ3fa). Consistently with the scope of the
iodoarene coupling partner, the methodology showed
compatibility with alcohols (3ea) among other functional
groups. Substituents at C7 were also found compatible, albeit
with decreased α:β regioselectivity (3ga). 3ꢀsubstituted
benzo[b]thiophenes could be coupled with 4ꢀiodotoluene 2a
generating the αꢀarylated products in remarkably high yields
(5aa and 5ca). Even, compound 5cr was obtained in a
noteworthy yield of 87% considering that both the bromine
atom and the methyl group at the orthoꢀposition of the
iodoarene are considerably sterically hindered. Moreover, the
methodology could be successfully applied to the synthesis of
α,βꢀbisarylated benzo[b]thiophenes (5aaꢀ5ab). Finally, the
same protocol was applied to substituted thiophenes 6aꢀe
obtaining the αꢀarylated products 7aaꢀ7ea in moderate to good
yields and selectivity (Table 4).20,21
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Table 4. Direct C–H Arylation of Substituted Benꢀ
zo[b]thiophene 1bꢀg or 4aꢀ4c with Iodoarene 2a and Subꢀ
stituted Thiophenes 6aꢀe with Iodoarene 2aa
a Reaction carried out on a scale of 0.75 mmol of 2. Isolated yields of Cꢀ2
products are given. C2/C3 ratios were determined by GCꢀMS analysis of
the crude reaction mixtures. Yields in brackets were determined by 1Hꢀ
NMR using 1,3,5ꢀtrimethoxybenzene as internal standard. b Performed on
c
d
a 20 mmol scale of 2a. Performed on a 0.25 mmol scale of 2a.
e
Performed at 50 °C. Isolated as an inseparable mixture 4:1 of C2:C3
arylated products. f Reaction carried out for 40 h.
to generate the αꢀarylated products in yields of 38% (3an) and
63% respectively (3ao). The methodology also exhibited
compatibility with meta (3apꢀ3aq) and orthoꢀsubstituted
iodoarenes (3arꢀ3ax), albeit with lower α:β regioselectivity in
the latter case.18 The reactivity of heterocyclic iodoarenes was
also investigated: in particular, 2,6ꢀsubstituted pyridine 2y was
found to react to a small extent (3ay) while Nꢀtosylꢀ5ꢀ
iodoindole generated the desired αꢀfunctionalized product in
excellent regioselectivity and 67% yield (3az). To further
highlight the mild conditions afforded by this protocol, we
tested the coupling between 1a and (S)ꢀNꢀbocꢀ4ꢀiodoꢀ
phenylalanine 2aaꞌ obtaining the desired product 3aaꞌ in 83%
a
Reaction carried out on a scale of 0.75 mmol of 2. Yields are given as
isolated. C3/C2 ratios were determined by GCꢀMS analysis of the crude
b
reaction mixtures. Isolated as an inseparable mixture 6:1 of C2:C3
arylated products. c 2r instead of 2a. d 2b instead of 2a. e Reaction carried
out using Pd(OAc)2 (0.8 mol %) and performed at 50 °C for 16 h.
f Reaction carried out using 1.0 equiv of 6 and 2.0 equiv of 2a with
Pd(OAc)2 (0.8 mol %) and performed at 50 °C for 16 h.
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Scheme 6. a) Same “excess” experiment; VTNA enables
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2.2. Mechanistic Considerations
2.2.1. Competition Experiments
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the determination of the order in b) Pd catalyst, c) benꢀ
zo[b]thiophene 1a, d) ArI 2a, e) NaOAc, a f) Ag2O. b
With the aim of gaining information on the mechanism, we
carried out a competition experiment between 4ꢀiodotoluene
2a and 1ꢀiodoꢀ4ꢀnitrobenzene 2k (Scheme 5a). The higher
reactivity of the more electron rich iodoarene 2a suggests that
the oxidative addition is reversible and happening before the
rate limiting step.9,22 A competition experiment between 3ꢀ
bromoꢀbenzo[b]thiophene 4c and 3ꢀmethylbenzo[b]thiophene
4b was also tested (Scheme 5b). The similar steric size of CH3
and Br (van der Waals radii of 1.85 and 1.97 Å (average),
respectively)22,23 allows extracting conclusions on the electronꢀ
ic effects of these substituents. Thus, the much higher reactiviꢀ
ty of the more acidic 4c suggests that the C–H activation is
rate limiting.25 Further evidence was obtained by measuring a
H/D KIE of 3.0 for this system, suggesting a rate limiting C–H
activation that is likely proceeding via a concerted metalation
deprotonationꢀlike process (Scheme 5c).11,12,26 This is in conꢀ
trast to the KIE of 1.0 measured for the C3ꢀarylation protocol.9
3
4
5
6
7
8
9
a) Same excess
b) Order 0 in Pd(OAc)2
"Time-adjusted" same
["excess"] conditions"
Standard conditions
0.8 mol %
0.4 mol %
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1
0.8
[3aa]
0
Same ["excess"]
[2a]
0
0
[Pd(OAc)2]0t
8
0
t (h)
11
c) Order 1 in 1a
d) Order 0 in 2a
4 equiv
2 equiv
0.5 equiv
0.8
1 equiv
Scheme 5. Competition Experiments
0.9
[3aa]
0
1.5 equiv
1.25 equiv
[3aa]
0
0
Σ[1a]1Δt
15
0
Σ[2a]0Δt
8
e) Order 0 in NaOAc
f) Order 0.5 in Ag2O b
0.375 equiv
0.5 equiv
0.75 equiv
0.6 equiv
0.4 equiv
0.5 equiv
0.6
0.8
[3aa]
0
[5ca]
0
0
[NaOAc]0t
8
0
Σ[Ag2O]0.5Δt
0.8
a In the graphs, equiv are referred to the amounts of reactants whose orders
are determined. For experimental details and unmodified temporal
reaction profiles, see Supporting Information. The kinetic run was
2.2.2. Kinetic Studies
b
performed with 4c instead of 1a, to give product 5ca.
To gain further information on the mechanism of this
reaction, we proceeded with the acquisition of kinetic data.
We elected to use the experimental design of Blackmond’s
reaction progress kinetic analysis (RPKA)27 and analyzed the
data with the variable time normalization analysis (VTNA)
graphical methods recently developed by Burés (Scheme
6).28,29 In order to use these tools, catalyst deactivation and
product inhibition cannot be present. Under the standard conꢀ
ditions, the same “excess” reaction analyzed with the timeꢀ
adjusted method reveals that the reaction was not affected by
these issues (Scheme 6a). We began the analysis with an inꢀ
vestigation on the order of the Pd catalyst. Similarly to our
previously reported discovery of Ag(I)ꢀmediated C–H activaꢀ
tion,11 an order of zero was obtained for Pd(OAc)2 at loadings
between 0.4 and 0.8 mol %. Given that the Pdꢀspecies are fully
soluble in the reaction conditions, these results imply that a
process external to the Pdꢀcatalytic cycle is rate limiting
(Scheme 6b),11 ,30 in agreement with our proposal
of a Agꢀmediated C–H activation of benzo[b]thiophene 1a
(Scheme 3, path B). An order of 1 in 1a and an order 0 in
iodoarene 2a (Scheme 6cꢀd) provide further support for this
hypothesis. The order of 1 in benzo[b]thiophene together with
the order zero in Pdꢀcatalyst suggests that Pd is not involved in
the C–H activation step. An order zero was obtained for
NaOAc suggesting that this species is not involved in the rate
limiting step (Scheme 6e). We speculate that NaOAc helps the
reaction by lowering the rate of insertion of the arylꢀPd comꢀ
plex III to the double bond of benzo[b]thiophene (to IV in
Scheme 3) in the path to C3 formation, thus favoring the C2
pathway;31 on the other hand, the rate from III to VI remains
controlled by the Ag(I)ꢀC–H activation rate limiting step and
therefore unaffected by NaOAc. Demonstrating the involveꢀ
ment of Ag in the C–H activation step of the catalytic process
proved to be nonꢀtrivial. Two practical issues were faced: 1)
the low solubility of Ag2O in HFIP and 2) when lowering the
rate of C2ꢀarylation process, C3ꢀarylation becomes competiꢀ
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tive again, producing a mixture of C2 and C3 which are exꢀ
1
2
3
4
5
6
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tremely difficult to deconvolute into mechanistic information
(Supporting Information, Figure S.7). These issues were overꢀ
come by changing the substrate to 3ꢀbromobenzo[b]thiophene
4c. This allowed us to measure an order 0.5 in Ag2O at conꢀ
centrations between 0.6 M and 0.4 M (Scheme 6f). This order
in Ag is consistent with an inactive dimeric resting state of the
type Ag2Xn in equilibrium with the active monomeric AgX
species. We speculate that AgOCH(CF3)2 could form in situ in
low concentrations by acidꢀbase reaction of Ag2O with HFIP
and could be responsible for the observed reactivity.32,33 Taken
together, these kinetic data point to a mechanism involving a
rateꢀlimiting Agꢀmediated C–H activation of 1a consistent
with our proposal in Scheme 3, path B.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
9
igor.larrosa@manchester.ac.uk
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Author Contributions
‡ These authors contributed equally to this work.
Notes
The authors declare no competing financial interests.
3. CONCLUSION
In conclusion, we have developed the first protocol for
the near room temperature αꢀarylation of benzo[b]thiophenes,
which also found application to the αꢀarylation of substituted
thiophenes. The excellent regioselectivity and mild conditions
of this methodology are derived from a novel approach that
utilizes Ag(I) to carry out C2ꢀselective C–H activation, before
transmetalation to Pd and subsequent C–C bond formation.
The use of very low concentrations of the Pd catalyst is possiꢀ
ble due to the key role played by Ag. D/H scrambling, compeꢀ
tition experiments, KIE and kinetic studies support a mechaꢀ
nism involving Ag(I)ꢀC–H activation.
ACKNOWLEDGMENT
We gratefully acknowledge the European Research Council
for a Starting Grant (to I.L.), the Engineering and Physical
Sciences
Research
Council
(EP/L014017/2
and
EP/K039547/1) and the Spanish MECD (grant FPU
13/05325, EST15/00774, to J. FꢀC.)
REFERENCES
(1) For selected applications of arylated benzo[b]thiophenes and thioꢀ
phenes, see: (a) Lu, R.ꢀJ.; Tucker, J. A.; Pickens, J.; Ma, Y.ꢀA.; Zinevitch,
T.; Kirichenko, O.; Konoplev, V.; Kuznetsova, S.; Sviridov, S.; Brahꢀ
machary, E.; Khasanov, A.; Mikel, C.; Yang, Y.; Liu, V; Wang, J.; Freel,
S.; Fisher, S.; Sullivan, A.; Zhou, J.; StanfieldꢀOakley, S.; Baker, B.;
Sailstad, J.; Greenberg, M.; Bolognesi, D.; Bray, B.; Koszalka, B.; Jeffs,
P.; Jeffries, C.; Chucholowski, A.; Sexton, C. J. Med. Chem. 2009, 52,
4481ꢀ4487. (b) Senthil Kumar, N.; Arul Clement, J.; Mohanakrishnan, A.
K. Tetrahedron 2009, 65, 822ꢀ830. (c) Bridges, T. M.; Kennedy, J. P.;
Hopkins, C. R.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett.
2010, 20, 5617ꢀ5622. (d) Segawa, Y.; Maekawa, T.; Itami, K. Angew.
Chem. Int. Ed. 2015, 54, 66ꢀ81. (e) Liger, F.; Bouhours, P.; GanemꢀElbaz,
C.; Jolivalt, C.; PelletꢀRostaing, S.; Popwycz, F.; Paris, J.; Lemaire, M.
ChemMedChem 2016, 11, 320ꢀ330. (f) RodríguezꢀCantó, P. J.; Martínezꢀ
Marco, M.; SánchezꢀRoyo, J. F.; MartínezꢀPastor, J. P.; Abargues, R.
Polymer 2017, 108, 413ꢀ422.
(2) (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359ꢀ1469. (b) de Meijere, A.; Diederich, F.
Metal-Catalyzed Cross-Coupling Reactions; WileyꢀVCH: Weinheim,
2004. (c) Seechurn, C. C. C. J.; Kitching, M. O.; Colacot, T. J.; Snieckus,
V. Angew. Chem. Int. Ed. 2012, 51, 5062ꢀ5085. (d) Colacot, T. J. New
Trends in Cross-Coupling: Theory and Applications; RSC: Cambridge,
2015.
(3) Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji,
A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951ꢀ1958.
(4) For [Pd] catalysis, see: (a) Nandurkar, N. S.; Bhanushali, M. J.;
Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett. 2008, 49, 1045ꢀ1048. (b)
Liégault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org.
Chem. 2009, 74, 1826ꢀ1834. (c) Tamba, S.; Okubo, Y.; Tanaka, S.;
Monguchi, D.; Mori, A. J. Org. Chem. 2010, 75, 6998ꢀ7001. (d) René, O.;
Fagnou, K. Adv. Synth. Catal. 2010, 352, 2116ꢀ2120. (e) Baghbanzadeh,
M.; Pilger, C.; Kappe, C. O. J. Org. Chem. 2011, 76, 8138ꢀ8142. (f)
Ghosh, D.; Lee, H. M. Org. Lett. 2012, 14, 5534ꢀ5537. (g) Zhao, L.;
Bruneau, C.; Doucet, H. Tetrahedron 2013, 69, 7082ꢀ7089. (h) DaoꢀHuy,
T.; Haider, M.; Glatz, F.; Schnürch, M.; Mihovilovic, M. D. Eur. J. Org.
Chem. 2014, 2014, 8119ꢀ8125. (i) Li, Y.; Wang, J.; Huang, M.; Wang, Z.;
Wu, Y.; Wu, Y. J. Org. Chem. 2014, 79, 2890−2897. (j) Luo, B.ꢀT.; Liu,
H.; Lin, Z.ꢀJ.; Jiang, J.; Shen, D.ꢀS.; Liu, R.ꢀZ.; Ke, Z.; Liu, F.ꢀS. Organ-
ometallics 2015, 34, 4881ꢀ4894. (k) Jakab, A.; Dalicsek, Z.; Soós, T. Eur.
J. Org. Chem. 2015, 2015, 56ꢀ59. (l) Korenaga, T.; Sasaki, R.; Shimada,
K. Dalton Trans. 2015, 44, 19642ꢀ19650. (m) Ouyang, J.ꢀS.; Li, Y.ꢀF.;
Shen, D.ꢀS.; Ke, Z.; Liu, F.ꢀS. Dalton Trans. 2016, 45, 14919ꢀ14927. (n)
Ahmed, J.; Sau, S. C.; P, S.; Hota, P. K.; Vardhanapu, P. K.; Vijaykumar,
G. ; Mandal, S. K. Eur. J. Org. Chem. 2017, 2017, 1004ꢀ1011. (o) Chikhi,
4. EXPERIMENTAL SECTION
General procedure: Pd(OAc)2 (0.4 mol %), silver oxide (1.0
equiv), NaOAc (0.5 equiv), aryl iodide 2 (1.0 equiv) and (subꢀ
stituted)ꢀbenzo[b]thiophene 1 or 4 or (substituted)ꢀthiophene 6
(2.0 equiv) were stirred in hexafluoroꢀ2ꢀpropanol (1 M) at 30
°C for 16 h. After this time, the resultant mixture was diluted
with EtOAc (5 mL) and filtered through a plug of silica. The
silica plug was flushed with EtOAc (30 mL) and the filtrate
was evaporated to dryness under reduced pressure. Purificaꢀ
tion via column chromatography afforded the desired arylated
(benzo)thiophenes 3, 5 or 7.
Representative example: 2-(p-tolyl)benzo[b]thiophene (3aa;
0.75 mmol scale reaction: Table 3). Benzo[b]thiophene 1a
(205 mg, 1.5 mmol, 2.0 equiv), 4ꢀiodotoluene 2a (165 mg,
0.75 mmol, 1.0 equiv), Pd(OAc)2 (0.4 mol %), silver oxide
(174 mg, 0.75 mmol, 1.0 equiv), and NaOAc (31 mg, 0.375
mmol, 0.5 equiv) were stirred in 0.75 mL of 1,1,1,3,3,3ꢀ
hexafluoroꢀ2ꢀpropanol (HFIP) at 30 °C for 16 h. After this
time, the resultant mixture was diluted with EtOAc (5 mL) and
filtered through a plug of silica. The silica plug was flushed
with EtOAc (30 mL) and the filtrate was evaporated to dryness
under reduced pressure. Product 3aa was then isolated by
column chromatography (hexane) as a white solid in 84%
1
yield (141 g, 0.63 mmol). Rf (hexane): 0.47; HꢀNMR (500
MHz, CDCl3): δ (ppm) 7.82 (d, J = 8.02 Hz, 1H), 7.76 (d, J =
8.02 Hz, 1H), 7.62 (d, J = 8.03 Hz, 2H), 7.51 (s, 1H), 7.37ꢀ
7.27 (m, 2H), 7.24 (d, J = 8.04 Hz, 2H), 2.40 (s, 3H); 13Cꢀ
NMR (101 MHz, CDCl3): δ (ppm) 144.7, 141.1, 140.0, 138.6,
131.8, 130.0, 126.7, 124.8, 124.4, 123.7, 122.6, 119.2, 21.6;
HRMS: calcd for C15H12S (M+), 224.0654; found, 224.0654;
Mp: 166ꢀ168 °C.
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S.; Djebbar, S.; Soulé, J.ꢀF.; Doucet, H. J. Organomet. Chem. 2017, 831,
(22) (a) Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131,
12898ꢀ12899. (b) Vinogradova, E. V.; Fors, B. P.; Buchwald, S. L. J. Am.
Chem. Soc. 2012, 134, 11132ꢀ11135.
55ꢀ63. For a bimetallic system involving [Pd]/[Cu] complexes, see: (p)
Yin, S.ꢀC.; Zhou, Q.; He, Q.ꢀW.; Li, S.ꢀW.; Qian, P.ꢀC.; Shao, L.ꢀX.
Tetrahedron 2017, 73, 427ꢀ431.
1
2
(23) Charton, M. J. Am. Chem. Soc. 1969, 91, 615ꢀ618.
3
4
5
6
7
8
9
(5) Do, HꢀQ.; Kashif Khan, R. M.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185ꢀ15192.
(6) Join, B.; Yamamoto, T.; Itami, K. Angew. Chem. Int. Ed. 2009, 48,
3644ꢀ3647.
(24) CH3 and Br present similar Taft’s ES steric parameters: −1.24 and
−1.16, respectively.
(25) (a) Shen, K.; Fu, Y.; Li, J.ꢀN.; Liu, L.; Guo, Q.ꢀX. Tetrahedron
2007, 63, 1568‒1576. (b) Gorelsky, S. I.; Lapointe, D; Fagnou, K. J. Am.
Chem. Soc. 2008, 130, 10848–10849 (c) Liégault, B.; Lapointe, D.; Caron,
L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009, 74, 1826ꢀ1834. (d)
Ueda, K.; Yanagisawa, S.; Yamaguchi, J.; Itami, K. Angew. Chem. Int. Ed.
2010, 49, 8946ꢀ8949.
(26) Importantly, D/H exchange was not observed in the KIE experiꢀ
ment with d1ꢀ1a. This is consistent with the transmetalation from the
benzo[b]thiophenylꢀAgꢀcomplex to Pdꢀintermediate III (Scheme 3) being
faster than the D/H exchange process, and a rate determining AgꢀCꢀH
activation.
(27) (a) Blackmond, D. G. Angew. Chem. Int. Ed. 2005, 44, 4302ꢀ4320.
(b) Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.; Futran, A.;
Emanuelsson, E. A. C.; Blackmond, D. G. J. Org. Chem. 2006, 71, 4711ꢀ
4722. (c) Baxter, R. D.; Sale, D.; Engle, K. M.; Yu, J.ꢀQ.; Blackmond, D.
G. J. Am. Chem. Soc. 2012, 134, 4600ꢀ4606.
(28) (a) Burés, J. Angew. Chem. Int. Ed. 2016, 55, 2028ꢀ2031. (b) Buꢀ
rés, J. Angew. Chem. Int. Ed. 2016, 55, 16084ꢀ16087.
(29) The temporal reaction profiles have been analyzed considering eiꢀ
ther [3aa] alone or in combination with [5aa] obtaining identical results.
For more details, see Supporting Information.
(30) (a) Pandey, R. N.; Henry, P. M. Can. J. Chem. 1975, 53, 2223ꢀ
2231. (b) Tanaka, Y.; Takahara, J. P.; Lempers, H. E. B. Org. Process
Res. Dev. 2009, 13, 548ꢀ554. (c) Yayla, H. G.; Peng, F.; Mangion, I. K.
McLaughlin, M.; Campeau, L.ꢀC.; Davies, I. W.; DiRocco, D. A.;
Knowles, R. R. Chem. Sci. 2016, 7, 2066ꢀ2073.
(31) A plausible explanation for NaOAc having the effect of reducing
C3ꢀarylation could be associated to the formation of ArPdXꢀspecies III
containing OAc as X, instead of OCH(CF3)2. Indeed, we had previously
shown (ref. 9) that “ArꢀPdꢀOCH(CF3)2”ꢀtype intermediates were essential
for achieving C3 regioselectivity, while addition of any carboxylate
species resulted in significantly reduced activity.
(7) For recent reviews on C–H functionalisation of αꢀ/βꢀarylation of
benzo[b]thiophenes and other heterocycles, see: (a) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem. Int. Ed. 2009, 48, 9792ꢀ9826. (b)
Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269ꢀ10310. (c) Roger, J.;
Gottumukkala, A. L.; Doucet, H. ChemCatChem. 2010, 2, 20ꢀ40. (d)
Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth. Catal. 2014, 356,
17ꢀ117. (e) Djakovitch, L.; Felpin, F.ꢀX. ChemCatChem 2014, 6, 2175ꢀ
2187. (f) Kazzouli, S. E.; Koubachi, J.; Brahmi, N. E.; Guillaumet, G. RSC
Adv. 2015, 5, 15292ꢀ15327. (g) Rossi, R.; Lessi, M.; Manzini, C.; Marianꢀ
etti, G.; Bellina, F. Adv. Synth. Catal. 2015, 357, 3777ꢀ3814. (h) Bheeter,
C. B.; Chen, L.; Soulé, J. F.; Doucet, H. Catal. Sci. Technol. 2016, 6,
2005ꢀ2049; (i) Badenock, J. C.; Gribble, G. W. In Advances in Heterocy-
clic Chemistry; Scriven, E. F. V.; Ramsden, C. A., Eds.; Elsevier: USA,
2016, pp. 99ꢀ136. (j) Maes, J.; Maes B. U. W. In Advances in Heterocyclic
Chemistry; Scriven, E. F. V.; Ramsden, C. A., Eds.; Elsevier: USA, 2016,
pp. 137ꢀ194. (k) Théveau, L.; Schneider, C.; Fruit, C.; Hoarau, C. Chem-
CatChem 2016, 8, 3183ꢀ3194. (l) Yin, S.; Zhou, Q.; He, Q.; Li, S.; Qian,
P.; Shao, L. Tetrahedron, 2017, 73, 427 – 431. (m) Komiyama, T; Miꢀ
nami, Y; Furuya, Y; Hiyama, T. Angew.Chem. Int. Ed. 2018, 57,1987ꢀ
1990.
(8) αꢀArylation of benzo[b]thiophenes at room temperature has been
previously claimed by Xu, Z.; Xu, Y.; Lu, H.; Yang, T.; Lin, X.; Shao, L.;
Ren, F. Tetrahedron 2015, 71, 2616ꢀ2621. However, a careful analysis of
1H and 13C NMR spectra provided in the Supporting Information reveal
that the regiochemistry was incorrectly assigned and the βꢀarylated benꢀ
zo[b]thiophenes were obtained instead. Indeed, when we attempted this
protocol, low yields of the βꢀarylated product were obtained exclusively.
(9) Colletto, C.; Islam, S.; JuliáꢀHernández, F.; Larrosa, I. J. Am. Chem.
Soc. 2016, 138, 1677ꢀ1683.
(10) We have previously shown that this transformation is likely to proꢀ
ceed via a Heckꢀtype Pd0/II pathway as that shown in Scheme 3a. See ref.
9.
(11) Whitaker, D.; Burés, J.; Larrosa, I. J. Am. Chem. Soc. 2016, 138,
8384ꢀ8387.
(12) Lotz, M. D.; Carnasso, N. M.; Canty, A. J.; Sanford, M. S. Organ-
ometallics 2017, 36, 165ꢀ171.
(13) Yunmi Lee, S.; Hartwig, J. F. J. Am. Chem. Soc. 2016, 138, 15278ꢀ
15284.
(14) While it is tempting to assume from this experiment that NaOAc is
accelerating the CꢀH activation step, this is not necessarily so. Subsequent
experiments (see Mechanistic Section) suggest that NaOAc is only accelꢀ
erating the H/D exchange step after the Ag(I)ꢀCꢀH activation (see Supꢀ
porting Information, section IVꢀ1, for a detailed explanation).
(15) The requirement of stoichiometric Ag2O arises from the secondary
role of the Ag as iodine scavenger (as depicted in Scheme 3).
(16) Trace amounts of C2/C3ꢀbisarylated product, 5aa, were also deꢀ
tected. See Supporting Information for details.
(17) The coupling between benzo[b]thiophene 1a and 4ꢀiodotoluene 2a
was tested using the standard conditions in the presence of N,Nꢀ
dimethylaniline (20 mol %) obtaining the desired product 3aa in only
traces.
(18) The lower C2:C3 selectivity observed when using orthoꢀsubstituted
aryl iodides could result from a more difficult transmetallation step beꢀ
tween the benzo[b]thiophenylꢀAg complex and the Ar–Pd III (Scheme 3),
thus favoring the formation of C3 arylated product. Nonetheless, no clear
regioselectivity trend depending on the steric and electronic properties of
the substituents has been observed.
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(32) Attempts at independently preparing AgOCH(CF3)2 by a variety of
methods led to decomposition products.
(33) For a reaction with a dimerization offꢀcycle equilibrium the order
on these species must be in the range 0.5 to 1. See. ref. 28(a).
(19) Racemization in the Stille coupling of a similar substrate has been
observed at temperatures above 70 °C.
(20) For recent examples of arylation of thiophenes, see: (a) Yin, S.;
Zhou, Q.; He, Q.; Li, S.; Qian, P.; Shao, L. Tetrahedron 2017, 73, 427ꢀ
431; (b) Natarajan, P.; Bala, A.; Mehta; B. Tetrahedron 2016, 72, 2521ꢀ
2526.
(21) No relevant side products and complete recovery of the starting
materials were observed.
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