Au–Ag Bimetallic Catalysis: 3-Alkynyl Benzofurans from Phenols via Tandem C?H Alkynylation/Oxy-Alkynylation

Article abstract of DOI:10.1002/anie.202016595

The development of new methodologies enabling a facile access to valuable heterocyclic frameworks still is an important subject of research. In this context, we describe a dual catalytic cycle merging C?H alkynylation of phenols and oxy-alkynylation of the newly introduced triple bond by using a unique redox property and the carbophilic π acidity of gold. Mechanistic studies support the participation of a bimetallic gold–silver species. The one-pot protocol offers a direct, simple, and regio-specific approach to 3-alkynyl benzofurans from readily available phenols. A broad range of substrates, including heterocycles, is transferred with excellent functional group tolerance. Thus, this methodology can be used for the late-stage incorporation of benzofurans.

Full text of DOI:10.1002/anie.202016595

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 10637–10642
International Edition: doi.org/10.1002/anie.202016595
German Edition: doi.org/10.1002/ange.202016595
Benzofuran Synthesis
Au–Ag Bimetallic Catalysis: 3-Alkynyl Benzofurans from Phenols via
À
Tandem C H Alkynylation/Oxy-Alkynylation
Long Hu, Martin C. Dietl+, Chunyu Han+, Matthias Rudolph, Frank Rominger, and
A. Stephen K. Hashmi*
Abstract: The development of new methodologies enabling
a facile access to valuable heterocyclic frameworks still is an
important subject of research. In this context, we describe
À
a dual catalytic cycle merging C H alkynylation of phenols
and oxy-alkynylation of the newly introduced triple bond by
using a unique redox property and the carbophilic p acidity of
gold. Mechanistic studies support the participation of a bimet-
allic gold–silver species. The one-pot protocol offers a direct,
simple, and regio-specific approach to 3-alkynyl benzofurans
from readily available phenols. A broad range of substrates,
including heterocycles, is transferred with excellent functional
group tolerance. Thus, this methodology can be used for the
late-stage incorporation of benzofurans.
Scheme 1. Metal-catalyzed synthesis of functionalized benzofurans;
a) common strategies; b) this work.
lyzed cyclization reaction of ortho-alkynyl phenols to produce
3-(a-alkoxyalkyl)benzofurans.[6a,g] In 2014, Blumꢁs group
reported an intramolecular gold-catalyzed alkoxyboration of
B
enzofuran, as a privileged structure, can be found in many
natural products and biologically active molecules.[1] In
addition, highly substituted benzofurans are also prevalent
in many leading drug candidates[2] and organic materials.[3]
Due to the immense importance of this target, several
efficient strategies have already been developed.[4,5] One of
the most successful modular strategies, which was established
over the past decades, is based on a tandem Sonogashira
coupling/5-endo-dig cyclization and a subsequent trapping of
the intermediate alkenyl–metal species by various electro-
philes (Scheme 1a).[6] The requirement of functionalized
precursors, such as ortho-halo or -alkynyl phenols, is a draw-
back. For example, in 2005, Fꢀrstner and Yamamoto inde-
pendently reported an elegant example of a platinum-cata-
À
C C multiple bonds, an impressive method for the prepara-
tion of benzofuran boronic acid derivatives, ideal precursors
for downstream transformations.[6b] Recently, Fensterbank
et al. developed a dual gold- and photo-induced alkynylative
ortho-cyclization to achieve 3-alkynyl benzofurans via a pho-
tosensitized oxidative addition.[6i] Despite the efficiency and
the synthetic potential of these strategies, the requirement of
pre-functionalized substrates is still disadvantageous in these
specialized protocols involving multistep procedures. Con-
sequently, there is still a high demand to develop efficient and
simple methods for the direct synthesis of functionalized
benzofurans.
Gold catalysis serves as a powerful tool in synthetic
organic chemistry,[7] in particular in the fields of heterocyclic
chemistry[8] and complex molecule synthesis.[9] Recently, the
potential of alkynyl gold(III) species to introduce alkyne
moieties as useful synthetic handles for further manipulations
was reported.[10] As part of our continuing efforts in gold
redox chemistry, we recently developed a ligand-enabled
oxidative addition of alkynylbenziodoxole as key to alkynyl
gold(III) complexes.[11] Based on this, we envisioned that an
intermolecular tandem process starting from simple phenols
might directly afford functionalized benzofurans, enabled by
a reactive alkynyl gold(III) species. To the best of our
knowledge, the direct synthesis of valuable 3-alkynyl benzo-
furans from readily available phenols is yet unknown. Two
challenges in a reaction of phenols with alkynyl gold(III)
complexes are: a) the sensitivity of phenols towards strong
oxidants, which can lead to homocoupling (as known for other
transition metals);[12] b) tailoring the conditions for the
generation of a reactive alkynyl gold(III) species in a catalytic
fashion. Herein, we report the development of an unprece-
dented direct synthesis of 3-alkynyl benzofurans by an Au–Ag
[*] L. Hu, M. C. Dietl,[+] C. Han,[+] Dr. M. Rudolph, Dr. F. Rominger,
Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im NeuenheimerFeld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University (KAU)
21589 Jeddah (Saudi Arabia)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016595.
ꢁ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution Non-Commercial
NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
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bimetallic-catalyzed cascade reaction from readily accessible
phenols and alkynylbenziodoxole reagents (Scheme 1b).
We started our evaluation of the reaction parameters by
using the phenol 1 and alkynylbenziodoxole 2 as model
substrates to examine the feasibility of the approach and to
optimize the reaction conditions (Table 1). After the adjust-
ment of various reaction parameters, the desired 3-alkynyl
benzofuran 4 was isolated in 94% yield in the presence of
5 mol% Ph3PAuCl/AgNTf2 and 20 mol% Phen in MeCN
under open-flask conditions at 458C. Control experiments
showed that gold, silver, and Phen all are essential for the
reaction. No reaction was observed with pre-activated
Ph3PAuNTf2 (by Celite filtration of the Ph3PAuCl/AgNTf2
mixtures) instead of an in situ activation (Ph3PAuCl/AgNTf2;
Table 1, entries 1 and 2). The need for the presence of silver
salts indicated a decisive role of silver, it was not only a simple
halide scavenger[13] (Table 1, entries 3–6). However, AgCl in
combination with a ligand (PPh3, IPr) as additive was not able
to promote the reaction, which indicated that free coordina-
tion sites at the silver are necessary to coordinate the Phen
ligand (Table 1, entries 7 and 8). Various gold(I) and gold(III)
complexes were also tested (Table 1, entries 9–11). Among
them, AuCl led to formation of 4 in 76% yield, and the
commonly used AuCl3 or IPrAuCl in the presence of AgNTf2
showed no catalytic activity. Other Phen-type ligands L1 and
L2 did not improve the reaction efficiency (Table 1,
entries 12–14). When the alkynylbenziodoxolone 3 was used
instead of 2, no conversion to 4 was observed (Table 1,
entry 15).
Under the optimized reaction conditions from Table 1 we
investigated the substrate scope of this tandem reaction. First,
we explored the scope with regard to the phenol moiety. A
variety of phenols smoothly reacted with alkynylbenziodox-
ole 2 providing the corresponding 3-alkynyl benzofurans in
good to excellent yields. As illustrated in Scheme 2, various
types of functional groups, for example, sulfonyl, carboxyl,
acyl, formyl, nitro, and cyano as well as F, Br, and Cl
substituents, were tolerated (4–10; 13–19).[14] Moreover,
disubstituted and trisubstituted phenols smoothly delivered
the products in excellent positional selectivity; only for an
ortho-substituted phenol a product mixture of 12 and 12’ was
obtained. Naphthols and 9-phenanthrol also delivered the
corresponding p-extended products in good yield and with
very good selectivity (20–23). Notably, hydroxy-substituted
heterocyclic systems were also compatible, providing the
products in good to excellent yields (24–28). Only some
electron-rich phenols, such as 4-methoxyphenol, were not
compatible (11); instead, a reductive homocoupling to 1,4-
diphenylbutadiyne was observed. A possible reason is that 4-
methoxyphenol due to the high pKa value (19.1 in DMSO)
cannot regenerate the bimetallic catalyst C (Scheme 5), while
the lower pKa value of ortho-C6H4IC(CF3)2OH allows the
catalyst regeneration (there is only a literature-known value
for hexafluoro-2-propanol, CH(CF3)2OH, which has a pKa of
17.9 in DMSO; due to the H substitutent it should be higher
than the pKa of ortho-C6H4IC(CF3)2OH with a sp2-C sub-
stitutent). And with the electron-withdrawing effect of two
meta-methoxy groups on the phenol, the pKa value of phenol
is increased. Therefore, product 17 was obtained in decent
yield. Various complex phenol derivatives of pharmaceutical
importance were examined next to prove the synthetic
potential of this strategy (29–31). A moderate amount of
the desired benzofuran product 30 was obtained from
Umbelliferone and 2, without affecting the lactone function-
ality of the coumarin moiety. Pleasingly, Nitroxoline, an
antibiotic that has been used by humans for many years,
reacted smoothly with 2 to provide 31 in excellent yield.
The scope with regard to the alkynylbenziodoxoles
reagents was studied with both aliphatic and (hetero)aromatic
ethynylbenziodoxole derivatives. These could successfully be
employed as precursors, providing a variety of 3-alkynyl
benzofurans in good to excellent yield (32–43).[15] In a one-pot
competition experiment of two different alkynylbenziodox-
oles, mainly the product 32 was obtained, in addition to
a small amount of 38; GC/MS shows only a trace of
a heterocoupling.
Table 1: Optimization of the reaction conditions.[a]
Entry
Catalytic system
Yield [%][b]
1
2
3
4
Ph3PAuCl/AgNTf2/Phen
Ph3PAuNTf2/Phen
94 (0)[c]
0
85
64
0
22
0
0
76
0
0
0
61
82
0
Ph3PAuNTf2/AgCl/Phen
Ph3PAuNTf2/AgBr/Phen
Ph3PAuNTf2/AgI/Phen
Ph3PAuNTf2/AgNTf2/Phen
Ph3PAuNTf2/Ph3PAgCl/Phen
Ph3PAuNTf2/IPrAgCl/Phen
AuCl/AgNTf2/Phen
IPrAuCl/AgNTf2/Phen
AuCl3/AgNTf2/Phen
Ph3PAuCl/AgNTf2/bpy
Ph3PAuCl/AgNTf2/L1
Ph3PAuCl/AgNTf2/L2
Ph3PAuCl/AgNTf2/Phen
5[d]
6[d]
7[d]
8[d]
9
10
11
12
13
14
15[e]
The obtained benzofurans still possess functional groups,
the alkynyl benzofuran was hydrogenated by formic acid
under palladium catalysis. Depending on the conditions either
the Z-alkene 44 or the E-isomer 45 was generated in excellent
yield.
Mechanistic evidence for the role of AgCl was gathered
by monitoring the conversion rates for different catalyst
combinations. As shown in Figure 1, equimolar amounts of
Ph3PAuCl/AgNTf2 or Ph3PAuNTf2/AgCl smoothly promoted
the reaction, while Ph3PAuNTf2 as single catalyst was inactive.
Notably, the addition of an equimolar amount of AgCl to the
mixture turned on the catalytic activity again and the reaction
[a] 1 (0.10 mmol), 2 (0.22 mmol), Ph3PAuCl/AgNTf2 (5 mol%), Phen
(20 mol%) in CH3CN (2 mL) at 458C under open flask conditions.
[b] Isolated yields. [c] No Ph3PAuCl, or AgNTf2, or Phen. [d] 24 h for the
reaction. [e] 3 instead of 2. Phen=1,10-phenanthroline.
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Scheme 2. General substrate scope with respect to phenols and alkynylbenziodoxoles. Reaction conditions: 1 (0.1 mmol), 2 (0.22 mmol),
Ph3PAuCl/AgNTf2 (5 mol%), and Phen (20 mol%) were stirred in CH3CN under open flask conditions at 458C; Yields refer to isolated product.
[a] 4 mmol scale.
proceeded smoothly in a good yield. As the solubility of AgCl
in acetonitrile at 258C is low (0.05 mgLÀ1),[16] a coordination
by the Phen ligand must take place. Thus, the active catalyst is
formed, probably a heterobimetallic complex. The lack of
reactivity with AgCl bearing an additional ligand (PPh3 or
IPr) can be explained by the missing free coordination site for
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Figure 1. 1H NMR monitoring of the reaction course with different
catalytic systems. Conditions: 1 (0.1 mmol), 2 (0.22 mmol), the
catalytic system (5 mol%), and Phen (20 mol%) were stirred in
CH3CN under open-flask conditions at 458C.
Scheme 4. Control experiments.
the Phen ligand in these complexes. This further underlines
that a PhenAgCl species is a crucial structural element in the
actually operating catalytic species. By ESI-MS measure-
ments of the Ph3PAuCl/AgNTf2/Phen system, an ion with
m/z = 781.0009 was detectable. A computational study of
different possible isomers originating from these components
was carried out. Complex A is the most stable of all calculated
species (see the Supporting Information). An analysis of this
phenol, which is the first step of the overall reaction, the step
leading to intermediates like 48 (Table 1, entry 2). It also
shows nicely that silver is not needed in the oxy-alkynylation
step and not needed in the benzofuran alkynylation. In the
absence of silver it is the [PhenAuPPh3]+ complex which is
able to undergo oxidative addition of 2, as previously
shown.[11a] This strongly indicates that the cascade starts
with the alkynylation of the phenol in the first step. It
excludes a scenario in which a C3-unsubstituted benzofuran
and gold(I) 3-benzofuryl complex are first formed which is
then alkynylated in the final step;[10a–c] instead, the oxy-
alkynylation is triggered by a bimetallic gold(III)-acetylide-
Ag complex followed by a subsequent reductive elimination.
Then the thermochemistry of the oxidative addition of the
used hypervalent iodo species to A was calculated (Figure 2).
Two reaction pathways were taken into consideration. On the
one hand the two-step oxidative addition starting from I
led us to the proposal of
a heterobimetallic species
Ph3PAuClAg(Phen) A as active catalytic species (Figure 1,
right side). In analogy to previous studies,[11a] we assumed that
an alkynyl gold(III) species might be a crucial intermediate in
the catalytic cycle as well. To verify this hypothesis, stoichio-
metric reactions with the preformed (Phen)gold(III) alkynyl
species B and 1 were conducted. But neither with nor without
AgCl, the desired product was detected (Scheme 3). This
indicated that the reaction is not proceeding through inter-
mediate B, which is then activated by the effect of AgCl, but
instead via the in situ-generated heterobimetallic Au/Ag
species A (introducing the Ag already at the AuI stage),
which serves as the active catalyst.
formed transition state II (DH = 15.1 kcalmolÀ1
; DG =
14.8 kcalmolÀ1). Afterwards species III (DH = 1.51 kcal
molÀ1; DG = 0.93 kcalmolÀ1) was obtained as an ionic pair
of a AuIII-complex with the alkyne from the hypervalent iodo
species and the corresponding benzylic alcoholate anion.
Ultimately, species IV (DH = À28.3 kcalmolÀ1
;
DG =
À27.6 kcalmolÀ1) was obtained as the final product of the
oxidative addition. Furthermore, a barrier-free concerted
pathway was found, which led to the same product IV. The
Scheme 3. Stoichiometric reactions with alkynyl gold(III) species B.
Next we reacted C3-unsubstituted benzofuran 47 and 2,
but the reaction failed to deliver any 3-alkynyl benzofuran 5
under the standard reaction conditions (Scheme 4a). In
addition, 2-alkynyl phenol 48 failed to afford the C3-
unsubstituted benzofuran (Scheme 4b); no conversion was
observed. In contrast, with or without AgCl, the reaction of 2-
alkynyl phenols 48 with 2 afforded the desired 3-alkynyl
benzofuran 5 in excellent yield (Scheme 4c). This indicates
that silver only is essential in the ortho-alkynylation of
Figure 2. DFT-computed free energies of the oxidative addition of the
hypervalent iodo species to heterobimetallic Au–Ag species A. Red:
concerted pathway; blue: stepwise pathway.
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same reaction was also calculated with Ph3PAuCl. This system
and draws attention to the actual role of AgCl in organic
did neither undergo cis nor trans oxidative addition of the
transformations.[17]
hypervalent iodo reagent towards a AuIII-species.
Geometry optimizations of the postulated active complex
A show a distance of of 3.17 ꢂ between gold and silver. Given
the van der Waals radii of both metals (r(Au) = 1.66 ꢂ and
r(Ag) = 1.72 ꢂ), this indicates a metallophilic interaction
between the two metal centers. This and the ligation of the
Ag(Phen) fragment lead to the increased reactivity of
complex A.[17]
On the basis of these observations and DFT calculations,
a plausible mechanism[18] is outlined in Scheme 5. First the
active heterobimetallic species Ph3PAuIClAg(Phen) (C) is
formed. This species then undergoes cis-oxidative addition
with 2 to afford alkynyl gold(III) compound D. At this stage,
attack of the phenol at the alkynyl AuIII species D, with
liberation of PhenAgCl and H+, delivers the quinone-type
intermediate E. Reductive elimination then affords the
alkynyl phenol F after tautomerization. In the second cycle
the alkyne in F is activated by AuIII-acetylide species D, which
triggers the intramolecular oxyauration to afford the gold(III)
complex H. Upon reductive elimination of H, the desired
product I is formed.[19] The reaction of the released catalyst G
then regenerates C with liberation of C6H4IC(CF3)2OH
(which leads to a low proton activity in the reaction mixture
and thus avoids proto-deauration processes).
Acknowledgements
L. Hu and C. Han are grateful to the CSC (China Scholarship
Council) for a Ph.D. fellowship. The authors acknowledge
support by the state of Baden–Wꢀrttemberg through bwHPC
and the German Research Foundation (DFG) through grant
no INST 40/467-1 FUGG (JUSTUS cluster). Open access
funding enabled and organized by Projekt DEAL.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Alkynylation · Au–Ag bimetallic catalysis ·
Benzofurans · Phenols
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Manuscript received: December 14, 2020
Revised manuscript received: January 27, 2021
Accepted manuscript online: February 22, 2021
Version of record online: March 30, 2021
10642 www.angewandte.org ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH Angew. Chem. Int. Ed. 2021, 60, 10637 –10642