Mild and selective base-free C-H arylation of heteroarenes: experiment and computation

Article abstract of DOI:10.1039/c6sc02595a

A mild and selective C-H arylation strategy for indoles, benzofurans and benzothiophenes is described. The arylation method engages aryldiazonium salts as arylating reagents in equimolar amounts. The protocol is operationally simple, base free, moisture tolerant and air tolerant. It utilizes low palladium loadings (0.5 to 2.0 mol% Pd), short reaction times, green solvents (EtOAc/2-MeTHF or MeOH) and is carried out at room temperature, providing a broad substrate scope (47 examples) and excellent selectivity (C-2 arylation for indoles and benzofurans, C-3 arylation for benzothiophenes). Mechanistic experiments and DFT calculations support a Heck-Matsuda type coupling mechanism.

Full text of DOI:10.1039/c6sc02595a

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Chemical Science
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Mild and selective base-free C–H arylation of heteroarenes:
Experiment and computation.
Hannes P. L. Gemoets,a Indrek Kalvet,b Alexander V. Nyuchev,a,c Nico Erdmann,a Volker Hessel,a
BF$Received 00th January 20xx,
Accepted 00th January 20xx
Franziska Schoenebeck,b* Timothy Noëla*
DOI: 10.1039/x0xx00000x
A mild and selective C–H arylation arylation strategy for indoles, benzofurans and benzothiophenes is described. The
arylation method engages aryldiazonium salts as arylating reagents in equimolar amounts. The protocol is operationally
simple, base free, moisture and air tolerant. It utilizes low palladium loadings (0.5-2.0 mol% Pd), short reaction times, green
solvents (EtOAc/2-MeTHF or MeOH) and is carried out at room temperature providing a broad substrate scope (47 examples)
and excellent selectivity (C-2 arylation for indoles and benzofurans, C-3 arylation for benzothiophenes). Mechanistic
experiments and DFT calculations support a Heck-Matsuda type coupling mechanism.
www.rsc.org/
Introduction
The ubiquity of the heterobiaryl motif in pharmaceuticals,
agrochemicals and materials illustrates their scientific and
commercial value.1 Traditionally, such moieties have been
prepared via cross-coupling strategies which require pre-
functionalized substrates.2 However, over the last decade,
transition metal-catalyzed C–H arylation protocols have been
developed to enable the formation of C–C bonds.3 In contrast
to classical cross-coupling chemistry, C–H arylation strategies
allow to directly functionalize simple heteroarenes.
The direct arylation of heteroarenes can be achieved via
radical pathways, e.g., visible light photoredox catalysis4 and
Meerwein arylations.5 However, these methods suffer from a
number of disadvantages, including long reaction times, large
excess of substrates, selectivity issues and limited substrate
scope. Recently, there has been an increase in the number of
new methods, particularly in the use of metal-catalyzed
processes.6 In particular, the work by Gaunt,7 Sames,8 Sanford,9
DeBoef,10 Glorius,11 Ackermann,12 Fagnou13 and Larrosa14 have
increased the number of useful C–H arylation transformations
to
enable
heteroaryl-(hetero)aryl
bond
formation.
Furthermore, these examples have deepened our fundamental
understanding of the underlying challenges inherent in such
processes. However, the state of the art is still far from ideal to
be competitive with classical cross coupling
Scheme 1: Pd-catalyzed C-2 C–H arylation of indoles
strategies, e.g. Suzuki-Miyaura cross coupling. Current hurdles
include harsh reaction conditions (i.e. high temperature),
necessity of stoichiometric amounts of oxidants and/or
additives, use of toxic solvent systems, limited selectivity and
high catalyst loadings (typical 5-10 mol%). Consequently, the
development of new, mild and broadly applicable C–H arylation
strategies are still highly desired.15 We anticipated that the
design of a mild and selective C-H arylation protocol for
heteroaromatics (i.e. indoles, benzofurans and
aDepartment of Chemical Engineering and Chemistry, Micro Flow Chemistry &
Process Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ
Eindhoven, The Netherlands. Email: t.noel@tue.nl
bInstitute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074
Aachen, Germany Email: franziska.schoenebeck@rwth-aachen.de
cDepartment of Chemistry, N. I. Lobachevsky State University of Nizhny Novgorod,
23 Gagarin Avenue, 603950 Nizhny Novgorod, Russian Federation.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Table 1: Optimization for the Pd-catalyzed C–2 arylation of 1-Methylindolea
areaction conditions: catalyst, 0.5 mmol heteroarene and 1.2 equiv. benzenediazonium tetrafluoroborate in 2.5 mL solvent at rt, 0.1 equiv. decafluorobiphenyl as internal
Entry
1
2
Catalyst (mol%)
Pd(OAc)2 (10.0)
Pd(OAc)2 (5.0)
-
Solvent
Reaction time
30 min
30 min
16 h
Yield GC-FID (%)
DMF
DMF
DMF
66
34
0
3
4
5
6
7
8
9
10
11
12
13
14e
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
catalyst (5.0)d
Pd(TFA)2 (5.0)
Pd2(dba)3 (2.5)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.2)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.2)
Pd(OAc)2 (0.5)
solventb
THF
THF
THF
THF
THF
THF
2-MeTHF
30 min
30 min
2 h
30 min
30 min
1 h
1 h
2 h
1 h
1 h
< 72
77; 76c
0
76
68
81
trace
87
89
78
EtOAc:2-MeTHF (1:1)
EtOAc:2-MeTHF (1:1)
EtOAc:2-MeTHF (1:1)
30 min
93; 90f
standard for GC-FID, open flask; bsolvent: H2O, AcOH, EtOAc, propylene carbonate, DMF, acetone, MeCN, Et2O, 1,4-dioxane, MeOH, EtOH, i-PrOH n-BuOH, DCM, DCE,
CHCl3, toluene; cSchlenk line techniques used; dcatalyst: 10% Pd/C, PdCl2, Cu(OAc)2, Cu(OTf)2, Pd[P(C6H5)3]4, (MeCN)2Pd(II)Cl2 and (C-3H5)2Pd(II)Cl2, PEPPSI-SIPr; e2 h
premixing of Pd(OAc)2 with 1-methylindole, 1.0 equiv. of benzenediazonium tetrafluoroborate used; fisolated yield.
benzothiophenes) could be of high interest for API synthesis 2-aryl-3-(arylazo)-1-methylindole (3aa), due to the uncatalyzed
(e.g. Bazedoxifene16, Saprisartan17 and Raloxifene18). Recently, electrophilic substitution reaction between the highly
Correia et al. described a Pd-based arylation of heteroarenes electrophilic nitrogen of the aryldiazonium salt and the C-3
using aryldiazonium salts.6i However, the protocol suffered position of 1-methylindole (Figure 1, b). Lowering the catalyst
from high catalyst loadings (10-20 mol% Pd), limited scope and loading to 5 mol% Pd(OAc)2 in DMF resulted in a significant drop
impractical reaction conditions (e.g. biphasic reaction in yield (34%). An overnight control experiment showed that no
conditions, large excess of reagents, high reaction product formation was observed in the absence of a palladium
temperatures). Herein, we describe the development of a mild catalyst (Table 1, Entry 3). Using polar protic solvents (e.g. i-
and selective palladium-based C–H arylation strategy (Scheme PrOH), resulted in general high reactivity and moderate yields.
1). Notable features of our open flask protocol are its
A
considerable amount of byproduct formation was
operational simplicity in conjunction with low catalyst loadings, consistently produced (see ESI). It was generally found that
broad substrate scope, green solvent system, and short reaction carrying out the reaction in less polar (aprotic) solvents (e.g.
times. No additional oxidants or additives are required. The DMF -> THF -> 1,4-dioxane) resulted in a suppression of the
strategy uses equimolar amounts or slight excess of byproduct formation. After a solvent screening, THF was
aryldiazonium salts as convenient arylating reagents.6l, 19 Kinetic considered the best solvent (77%), combining both the desired
studies and DFT calculations suggest that a Heck-Matsuda type reactivity and selectivity (Table 1, Entry 5).
A
control
mechanism is operational under our reaction conditions.
experiment, using Schlenk techniques, indicated that the
catalyst was not affected by air and moisture (Table 1, Entry 5).
Therefore, all the following experiments could be performed as
open-flask reactions, making this procedure appealing for
future scale up. A catalyst survey demonstrated that only
Pd(OAc)2, Pd(TFA)2 and to a lesser extent, Pd2(dba)3 were active
catalysts for this chemical transformation (Table 1, Entries 6-8).
The use of Pd(OAc)2 was preferred over Pd(TFA)2 due its cost
efficiency and stability. Further optimization studies showed
that it was possible to lower the catalyst loading further to 0.5
mol% in THF (Table 1, Entry 9). An even lower catalyst loading
resulted in only trace amounts of product (Table 1, Entry 10).
Results and discussion
Optimization of Reaction Conditions.
We commenced our optimization studies with the Pd-catalyzed
C–H arylation of 1-methylindole (1a), which was reacted with
1.2 equivalents of benzenediazonium tetrafluoroborate (2a) in
the presence of 10 mol% Pd(OAc)2 in DMF. A satisfying yield of
66% for 1-methyl-2-phenylindole (3a) was obtained within only
30 minutes reaction time at room temperature (Table 1, Entry
1). Main byproducts were 3-(arylazo)-1-methylindole (1aa) and
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Finally, 2-MeTHF was evaluated. This solvent is recognized as a
green solvent for synthetic organic chemistry, since it can be
readily produced from furfural, a common biomass material.20
Satisfyingly, 2-MeTHF showed an even better selectivity for the
desired product (87%), although an increased reaction time of
2 hours was required to obtain full conversion (Table 1, Entry
11). Continued optimization studies with green solvents
revealed that the reaction time could be halved by using
EtOAc:2-MeTHF (1:1) as solvent mixture (Table 1, Entry 12).
Indeed, this solvent combination proved to be superior as it
allowed to further lower the catalyst loading to 0.2 mol%
Pd(OAc)2 (Table 1, Entry 10 vs 13). However, in the case of 0.2
mol % Pd(OAc)2, a significant increase of 1aa and 3aa was
observed, since reactivity to the desired arylation is diminished.
Therefore, 0.5 mol% Pd(OAc)2 was considered to be optimal.
Parallel with our optimization studies, a series of reaction
progress kinetic experiments were performed to shed more
light on the observed catalyst induction period. Unusual kinetics
has often been reported in the field of C–H functionalization,
but has seldom been investigated.21 Therefore, in order to get a
more realistic view of this activation period, we monitored a
series of reactions. As can be seen from Figure 1a, an induction
period of approximately 50 minutes was present in the case of
Pd(OAc)2 (Figure 1a, blue series). As soon as the reaction kicks
off (>50 min), an initial acceleration is observed, hence the S-
curve behavior. It was postulated that a possible activation
period could be present between catalyst and substrate.
Therefore, premixing experiments were conducted. It was
found that premixing 1-methylindole with Pd(OAc)2 (0.5 mol%)
in EtOAc:2-MeTHF (1:1) for 2 hours could overcome this
observed induction period (Figure 1a, red series). We surmised
that Pd(II) is first reduced to a homogeneous Pd(0) complex and
is stabilized by either the π-donating character of 1-
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DOI: 10.1039/C6SC02595A
-
methylindole and/or by the ligand exchange of OAc with 2-
MeTHF.22 Indeed, a reaction performed with Pd2(dba)3 as a
stable homogenous Pd(0) substitute showed that neither an
induction period nor an initial acceleration is taking place
(Figure 1a, green series). However, lower yields were obtained
with Pd2(dba)3. This result gives us a first glimpse of the possible
catalytic mechanism at hand, indicating that palladium in its
homogeneous zero state can act as an active catalyst.
As expected, the product 3a was even more prone to Figure 1: a) Yield as function of time. In case of Pd(OAc)2 with no premixing (blue series),
1.1 equiv. of benzenediazonium tetrafluoroborate was used. b) Observed side-reactions
occurring in excess of benzenediazonium tetrafluoroborate.
undergo the side reaction (i.e. electrophilic substitution
reaction) with benzenediazonium salt, as the inductive effect of
the phenyl substituent makes the C-3 position more
tetrafluoroborate) was used. As a result, 90% of the desired
product could be isolated (Table 1, Entry 14). Note that the
reaction time could be halved again, to approximately 30
minutes, when using the premixing strategy. In addition, a
slightly higher selectivity was acquired since side reactions were
minimized. For more information regarding reaction
optimization and reaction progress analysis, we refer to the
Electronic Supporting Information (ESI).
nucleophilic.23 This was especially noticed when a slight excess
of benzenediazonium tetrafluoroborate was used (Figure 1a,
blue series). A drop of approximately 10% yield was observed
after prolonged reaction time, which accounts for the 0.1
equivalent excess. To counteract this consecutive reaction, an
equimolar amount (1.0 equiv. benzenediazonium
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Mechanistic Studies: DFT calculations and experimental
investigations.
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DOI: 10.1039/C6SC02595A
Since heteroarenes are good nucleophiles, it would be
reasonable to assume a mechanism in which Pd(II) acts as an
electrophile, consistent with numerous literature proposals in
the context of C-H functionalization.8a, 24 Similar to the SEAr,
these reactions are expected to be C-3 selective for indoles.
However, our methodology yields C-2 arylated indoles
selectively and would hence require a subsequent C-3/C-2
isomerization. In this context, Gaunt and co-workers showed
that the presence of acid would facilitate a switch from C-3 to
C-2 in the Pd-catalyzed C-H olefination of indoles,24 proposing
that under acidic conditions C-3 deprotonation of the indole
moiety would be slowed. However such a scenario appears
unlikely in our case. For instance, progress 1H-NMR, with
equimolar quantities of Pd(OAc)2 and 1-methylindole in d8-THF,
showed that neither the HC-2 or HC-3 peaks of 1-methylindole
were affected (see ESI section 3.1.1).25
Therefore, the employed Pd(OAc)2 likely serves as a pre-
catalyst and is reduced to Pd(0) during the initiation period.
Additionally, since we have shown that Pd(0) is catalytically
active without any induction period (Table 1, Entry 8), it is
reasonable to assume that the reaction proceeds via a
Pd(0)/Pd(II) catalytic cycle.26 This cycle starts with an initial
oxidative addition of the highly activated aryl diazonium salt to
Pd(0) to yield
a cationic Pd(II) complex which should
subsequently serve as electrophile in the reaction with the
substrate (Scheme 2, I). The overall product selectivity would
then again be determined by the C-3 to C-2 migration of Pd.24
However, our efforts to computationally locate the C-2 Pd
complex yielded a structure that is 9.1 kcal/mol higher in energy
than the preferred η2 π-complex Int1 (Figure 2), suggesting the
migration to be disfavored.27
Intermediate Int1 might alternatively undergo a Heck-type
carbopalladation reaction.28 Our calculations suggest this
process to be energetically feasible, being characterized by a
Figure 2: Heck-type carbopalladation pathway and the prediction of selectivity via its
transition states at the CPCM (THF) M06L/def2TZVP // wB97X-D/6-31G(d) SDD level of
theory.31 Coordination by two THF molecules was found to be the preferred ligation state
relatively facile free energy barrier of 17.5 kcal/mol (Figure 2). of Pd.29 Free energies are shown in kcal/mol.
Thus, we subsequently calculated the expected selectivities (C-
deprotonation rearomatisation could occur.14a, 28b, 32 While that
step may also be involved in our case, due to the ionic and
complex nature of the intermediates involved, an adequate
computational description of the system is associated with a
3
versus C-2) for C-H arylation for a carbopalladation
mechanism. We considered several possible solvent
coordinations to the cationic Pd, indicating that the
coordination of two THF molecules is likely preferred.29 Our
computed selectivities are in agreement with experiments.
Complete C-2 selectivity was experimentally observed for 1-
methylindole and benzofuran, consistent with our
computational results (ΔΔG‡ = 2.4 kcal/mol and 0.7 kcal/mol in
favor of C-2, respectively).30 By contrast, benzothiophene
yielded the C-3 arylated product exclusively, which was also
reproduced by computations (ΔΔG‡ = 1.9 kcal/mol in favor of C-
3), (see Figure 2).
The carbopalladation step in the traditional Heck-type
reaction would be followed by the syn-β-hydride elimination.
Due to the rigidity of the ring system, however, there is no
possibility for the conventional syn-β-hydride elimination from
the formed intermediate Int2. In contrast, it has been previously
suggested that a base or solvent assisted anti-β-
1
number of difficulties.28b, 33 However, in situ H and 19F NMR
analysis of the reaction have given us first insights into the likely
nature of the processes involved (see ESI section 3.1.2 for
detailed description). The data indicates that additional signals,
assigned as BF3∙2Me-THF and HF, are appearing in 19F NMR
spectrum at the same rate as the product 5b. Moreover, when
using an alternative counterion for the aryldiazonium salt (e.g.,
4-methoxybenzenediazonium mesylate), no product was
-
observed (Table 2, 3h). It is therefore hypothesized that the BF4
counterion of the aryldiazonium salt plays a non-innocent role
in the reaction mechanism, i.e. acting as a pseudo-base in the
anti-β-deprotonation rearomatisation step. Moreover, a crude
1H-NMR taken from the reaction (using
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Scheme 2: a) Proposed Pd(0)/Pd(II) Heck-Matsuda type cycle for the C–2 arylation of for 1-methylindole. b) Observed SN1 side-reaction in case of benzofuran in MeOH.
THF-d8 as solvent) indicates that the lost proton appears of 1-methylindoles and 1.0 mol% of Pd(OAc)2 for NH-indoles. A
quantitatively as a broad signal at 9.0 ppm.
Alternatively, a radical mechanism could be envisioned for of substituted aryldiazonium substrates
this transformation. However, a large excess (5 – 100 equiv.) of successfully coupled with 1-methylindole. Indole arylation with
the heteroarene substrate is generally required for satisfying aryldiazonium salts bearing alkyl substituents (3c-g, 4a-b
1:1 mixture of EtOAc:2-MeTHF was used as solvent. A broad set
(
3a-y could be
)
)
results under such conditions. In our case, optimal results were proceeded well for both N-protected and free indoles, even in
achieved with equimolar quantities. In addition, test reactions the presence of sterically demanding ortho-methyl substituents
via the radical pathway34 did not lead to the desired product.
(3c, 3e). When using the more sterically hindered
Moreover, radical scavenging tests failed to trap any radical mesitylenediazonium tetrafluoroborate as arylating agent, a
intermediates (see ESI for details). Finally, in radical chemistry, mixture (C-2 and C-3 arylated product) was found for both the
mixtures of C-2 and C-3 arylation are frequently observed,35 N-methylated and the free indole (3f
, 4c). Selectivity towards
while our system displays complete selectivity.
the C-3 arylated product was prevalent in 4c (C-2:C-3 1:3.3). For
all other reactions, complete selectivity towards the C-2
arylated product was observed. Next, a scope of aryldiazonium
Synthetic Scope: Heteroarenes and Aryldiazonium Salts.
With the optimized conditions in hand, we next explored the salts, containing hydroxy-, phenoxy- and methoxy-substituents,
scope of our developed methodology on indoles (Table 2). was explored (3h-p). It was demonstrated that aryldiazonium
These substrates were reacted with an equimolar amount of salts bearing a free hydroxyl group, showed some reactivity,
aryldiazonium salts in the presence of 0.5 mol% Pd(OAc)2 in case although in a lower yield (3p
,
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Table 2: Scope for the C–2 arylation of indolesa
areaction conditions: 0.5 – 1.0 mol % Pd(OAc)2, 1.0 mmol heteroarene and 1.0 equiv. aryldiazonium salt in 5 mL EtOAc:2-MeTHF (1:1) at rt, open flask, 2 h premixing of
c
Pd(OAc)2 with heteroarene; bPd2(dba)3 as catalyst, 1 h reaction; 1 mol % Pd(OAc)2, 1.2 equiv. aryldiazonium salt; d4-methoxybenzenediazonium mesylate was used;
egram-scale experiment (10.0 mmol) yielded 2.47g (83%), 4 h reaction time; f1 mol% Pd(OAc)2; g2 mol % Pd(OAc)2; h2 mol % Pd(OAc)2, 1.2 equiv. aryldiazonium salt; i1.2
equiv. aryldiazonium salt at 40 °C; *no full conversion obtained; j0.01 M and 100 mol % Pd2(dba)3 was used;
16%). A para-phenoxy group as electron-donating substituent coupling chemistry via C–O activation.36 In addition,
on the aryldiazonium salt resulted in good reactivity (3o, 79%). heterocyclic aryldiazonium salts were tolerated in this protocol:
Moreover, all methoxy-containing aryldiazonium salts (3h- 3q was obtained in a moderate yield (34%) overnight, while for
n) showed good to excellent reactivity (69-93%), except for 3l 3r, a good yield (71%) was acquired within 1 hour reaction time.
where no full conversion could be obtained. The yields obtained Notably, in case of free NH-indoles (4a-d), an ortho-methyl
for compounds 3h-n showcase the applicability of our substituent on the aryldiazonium salt proved necessary to avoid
methodology for the C–2 arylation of indoles with arylating significant by-product formation (electrophilic substitution).
agents bearing methoxy-substituents, which are often reported However, it was found that by blocking the C-3 position of the
8b, 9b
as cumbersome.7,
These substituents are functional NH-indole (i.e., via methylation) this side-reaction could be
handles which can be engaged in nickel-catalyzed cross- completely avoided
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Table 3: Scope of aryldiazonium tetrafluoroborate on benzofuran and benzothiophenea
(
4ea vs 4e).
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Next, we explored a more challenging class of aryldiazonium
salts bearing weakly (e.g., F) to highly electron-withdrawing
(e.g., NO2) substituents (3s-y). Gratifyingly, 4-fluoro- and 3-
iodobenzenediazonium tetrafluoroborate readily reacted with
1-methylindole
(3s, 3w). The latter (3w) is particularly
appealing, since it indicates that palladium undergoes oxidative
addition at the electrophilic diazonium site (instead of breaking
the C–I bond) at room temperature. In contrast, aryldiazonium
salts bearing m-CF3 (3ta), p-NO2 (3ua), o-Cl (3va) and p-Br (3xa),
as substituents did not deliver any arylated product when 1-
methylindole was used as the substrate. It was observed that
such aryldiazonium salts were too prone for electrophilic
substitution reactions, resulting in the rapid formation of 3-
(arylazo)-1-methylindoles (see Figure 1b). However, as for the
NH-indole case, this side reaction could be efficiently overcome
by blocking the C-3 position. Consequently, the arylation scope
could be expanded to electron-withdrawing substituents (3t
3u 3v 3x) with high to excellent yields of the desired product
(80-92%). This trend was also observed when aryldiazonium
salts bearing an acyl moiety were used (3ya and 3y 58% of the
,
,
,
)
:
target product (3ya) was obtained for the 1-methylindole while
an improved result was obtained for the C-3 methylated indole
(80% yield, 3y).
Subsequently, several indole derivatives were subjected to
the
tetrafluoroborate as a benchmark coupling partner. For 5a and
5c the reaction proceeded smoothly under equimolar
conditions. 5d proved more challenging (22% yield) due to the
electron-withdrawing nature of the methyl carboxylate
reaction
conditions
using
benzenediazonium
areaction conditions: 0.5 mol % Pd(OAc)2, 1.0 mmol heteroarene and 1.2 equiv.
aryldiazonium tetrafluoroborate in 5 mL MeOH at rt, open flask, after full conversion:
reflux with 5.0 equiv. acetyl chloride for 15 min; b2.0 mol % Pd(OAc)2, 2.0 equiv.
aryldiazonium tetrafluoroborate at 40 °C.
,
substituent, rendering it
a less nucleophilic substrate.
Interestingly, an experiment with 1,2-dimethylindole and
benzenediazonium salt, showed that no C-3 arylated product
could be formed over 5 hours. Instead, the substrate was fully
converted to the electrophilic substituted product 1bb (93%
30 minutes) while maintaining its selectivity (6e, 81%). The use
of the protic solvent MeOH resulted in the formation of 2-aryl-
3-methoxy-2,3-dihydrobenzofuran (6ee). It was speculated that
6ee was formed from the proposed carbopalladation
intermediate II through a SN1 mechanism, hence the syn/anti
diastereomeric mixture observed (Scheme 2, b). However, a
simple work up procedure, consisting of 15 minutes reflux
under acidic conditions (i.e. acetyl chloride), turned out to be
sufficient to eliminate MeOH from the compound, resulting in
the desired product in overall high yield. Benzofuran could be
readily coupled with benzenediazonium tetrafluoroborate in
good yield (6a, 70%).
Next, we carried out several reactions by coupling
benzofuran with several halogenated aryldiazonium
tetrafluoroborates (6b-h). Satisfyingly, all reactions proceeded
smoothly in the presence of only 0.5 mol% Pd(OAc)2, thus
showcasing the mild reaction conditions of this protocol.
Finally, we turned our attention towards a more challenging
yield). Moreover, during
a
control experiment with
stoichiometric amount of Pd2(dba)3, no 1bb was formed. Thus
indicating that the benzenediazonium salt preferably
underwent oxidative addition (see ESI section 3.3).
Next, a gram scale experiment was conducted to test the
scalability of this mild procedure. The reaction was carried out
with equimolar quantities of reactants (10 mmol) and 0.5 mol%
Pd(OAc)2 in 2-MeTHF. With a slightly longer reaction time of 4
hours, a satisfying yield of 83% (2.47 g) of 3k was achieved
under open flask conditions.
Having established a good coupling protocol for indoles, we
examined subsequently the scope of benzofuran (1i) with
various aryldiazonium salts (Table 3). Since benzofuran is not
prone to electrophilic substitution, MeOH could be used as a
more reactive solvent (see ESI). These results are in correlation
with literature.19b Felpin et al, demonstrated with DFT and
experimental results that the cationic palladium intermediates
in the Heck-cycle are exoergic with MeOH as solvent.37
Moreover, it was observed that the addition of 1.0 equivalent
of TFA resulted in an impressive rate acceleration (overnight to
heteroarene, i.e. benzothiophene
(1j) (Table 3). Being
benzothiophene the least nucleophilic heteroarene
investigated herein, it was necessary to use slightly higher
catalyst loadings (2.0 mol %) and 2.0 equivalents of
aryldiazonium salt in order to achieve full conversion. Operating
at 40 °C was decisive to obtain a good yield for both 7a (80%)
and 7b (73%). In agreement with literature and conducted DFT
calculations (see above), we observed a
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Scheme 3: Synthesis of the drug precursor 8a of Saprisartan.
complete shift in selectivity from C-2 to C-3 arylation. For additives are required. The substrate scope is broad and
compound 7a, a significant improvement in yield (80% vs. 69%) displays excellent selectivity (C-2 arylation for indoles and
and a reduction in reaction time (16 h vs. 96 h) was observed, benzofurans, C-3 arylation for benzothiophenes). To illustrate
highlighting the relevance of our mild protocol.11b Taken the efficacy of this procedure, a key intermediate (8a) for the
together, this C–H activation protocol for the direct arylation of drug Saprisartan was synthesized, comparing positively to the
heteroarenes provides a convenient pathway towards a broad patented process (70% vs 11%). Mechanistic experiments and
range of heteroaromatic arylated derivatives.
DFT calculations support a Heck-Matsuda type coupling
mechanism. Moreover, first experimental results indicate that
BF4 anions could be involved in the anti-β-deprotonation
Application: Synthesis of the Drug Precursor of Saprisartan.
-
To further illustrate the efficacy of this mild strategy, we applied rearomatisation step of the catalytic cycle. We expect this
the C–H arylation process to the synthesis of methyl 2-(5- protocol will find widespread application due to its mild
methylbenzofuran-2-yl)benzoate (8a) (Scheme 3). Compound character and excellent selectivity.
8a is a key intermediate in the total synthesis of
Acknowledgements
Saprisartan, an approved drug belonging to the sartan family.17 Financial support is provided by the Dutch Science Founda-tion
Sartans act as AT1-antagonists and are among the most (NWO) via an ECHO grant (Grant No. 713.013.001) and a VIDI
prescribed drugs for the treatment of hypertension and hearth grant for T.N. (Grant No. 14150). We also acknowledge the
failure.38 Our mild procedure allowed to successfully isolate the European Union for a Marie Curie CIG grant for T.N. (Grant No.
key intermediate 8a in 70% yield, and compared positively to 333659) and an ERC Advanced Grant for V.H. (Grant No.
the patented process, which required four consecutive steps for 267443).
the same transformation with an overall low yield of 11%.17, 39
IK and FS gratefully acknowledge the computing time granted
by the JARA-HPC “Vergabegremium" on the RWTH
Bull Cluster in Aachen (Grant JARA0091). HG and TN thank
Cecilia Bottecchia (TU/e) for helping with NMR analysis and Bart
Hendricks (TU/e) for helping with the synthesis of aryldiazonium
salts.
Conclusion
In summary, we have developed a mild and selective C–H
arylation of heteroarenes, including indoles, benzofurans and
benzothiophenes, with aryldiazonium salts. The protocol is
operationally simple and insensitive to air and moisture. It
utilizes low palladium loadings (0.5-2 mol% Pd), short reaction
times, green solvents (EtOAc/2-MeTHF or MeOH) and is carried
out at room temperature. Notably, no oxidants or other
We would like to thank referee 2 for stimulating discussions
during the revision stage of this manuscript.
Notes and references
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30 30Benzofuran was reacted in MeOH, which offers various
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