S,O-Ligand-Promoted Pd-Catalyzed C?H Olefination of Anisole Derivatives

Article abstract of DOI:10.1002/ejoc.202100737

The C?H olefination of substituted anisole derivatives by a Pd/S,O-ligand catalyst is reported. The reaction proceeds under mild conditions with a broad range of substituted aryl ethers bearing both electron donating and withdrawing substituents at ortho,

Full text of DOI:10.1002/ejoc.202100737

Communications
doi.org/10.1002/ejoc.202100737
S,O-Ligand-Promoted Pd-Catalyzed CÀ H Olefination of
Anisole Derivatives
Verena Sukowski,[a] Wen-Liang Jia,[a] Rianne van Diest,[a] Manuela van Borselen,[a] and
M. Ángeles Fernández-Ibáñez*[a]
The CÀ H olefination of substituted anisole derivatives by a Pd/
S,O-ligand catalyst is reported. The reaction proceeds under
mild conditions with a broad range of substituted aryl ethers
bearing both electron donating and withdrawing substituents
at ortho, meta and para positions. Aryl ethers are used as
limiting reagents and good yields and site selectivities are
observed. The methodology is operationally simple and can be
performed under aerobic conditions.
Figure 1. Representative bioactive alkenylated aryl ethers.
Aryl ethers are common structural motifs in natural products,
organic functional materials and drug molecules.[1] In particular,
alkenylated aryl ethers are present in several bioactive com-
pounds and therefore the introduction of such functionalities is
of great interest in organic synthesis (Figure 1).[1c,d] Although the
Heck reaction is an effective method to introduce alkenyl
moieties in aryl ethers, it suffers from the disadvantage of
requiring prefunctionalized arenes. In the last two decades,
metal-catalyzed CÀ H functionalization reactions have emerged
as a powerful synthetic tool to efficiently functionalize organic
molecules since no prefunctionalization of the starting materials
is required.[2] Using this approach, a wide variety of function-
alities have been introduced in anisole derivatives using differ-
ent transition metals.[3] In this regard, the CÀ H olefination of aryl
ethers have been realized using Pd-catalysis. However, in the
vast majority of these examples, an excess of arene is required,
limiting the broad applicability of these methodologies in
complex molecules.[4] Recently, ligand development has shown
to enhance the reactivity and site-selectivity of these processes,
allowing to use only stoichiometric amounts of arene.
In this context, three catalytic systems based on the use of i)
2-pyridone ligand (Scheme 1a),[5] ii) a dual ligand system,
pyridine and mono-N-protected amino acid (Scheme 1b),[6] and
iii) a S,O-ligand, which was reported by our research group,
have been described (Scheme 1c).[7] However, these examples
mainly focusses on simple arenes and little attention has been
[a] V. Sukowski, W.-L. Jia, R. van Diest, M. van Borselen, Prof. M. Á. Fernández-
Ibáñez
Van’t Hoff Institute for Molecular Sciences
University of Amsterdam
Science Park 904, 1098 XH Amsterdam, The Netherlands
E-mail: m.a.fernandezibanez@uva.nl
Scheme 1. Pd-catalyzed CÀ H olefination of aryl ethers.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100737
© 2021 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution License, which permits use, distribution and
paid to aryl ethers. Recently, a dual catalytic system based on
reproduction in any medium, provided the original work is properly cited.
the combination of a mono-protected amino acid and a S,O-
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doi.org/10.1002/ejoc.202100737
Table 1. Scope of aryl ethers.[a]
ligand for Pd-catalyzed CÀ H olefination of aryl ethers has been
reported (Scheme 1d).[8]
The reaction proceeds using 2 equiv. of aryl ether in the
presence of both AgOAc and K2S2O8 in AcOH and shows broad
substrate scope. However, in our hands we were unable to
reproduce some of the results using substituted anisoles.[9] To
this end, a new catalytic system based on bidentate nitrogen
ligands has been successfully applied in the CÀ H olefination of
aryl ethers. However, aryl ethers bearing electron withdrawing
substituents were not efficiently olefinated (Scheme 1e).[10]
Overall, a general method for Pd-catalyzed CÀ H olefination
of aryl ethers is still elusive. Herein, we report the CÀ H
olefination of a broad range of aryl ethers by Pd/S,O-ligand
catalyst (Scheme 1f). The reaction proceeds under mild con-
ditions with synthetically useful site-selectivities for a broad
range of aryl ethers. Ortho-substituted aryl ethers provide
mainly the para-olefinated products while para-substituted
anisoles afford primarily the ortho-substituted ones. For meta-
substituted anisoles, the major regioisomer depends on the
stereoelectronic character of the substituent. In addition, differ-
ent activated olefins are successfully introduced, and the
catalytic system is compatible with the use of oxygen as the
sole oxidant.
Starting from our initial report on the CÀ H olefination on
non-directed arenes, including anisole, using 2-ethy-2-(phenyl-
thio)-acetic acid (L1) as S,O-ligand,[7a] we decided to focus on
the CÀ H olefination of substituted anisole derivatives. The
reaction in the presence of 10 mol% of Pd(OAc)2/L1, 1 eq. of
t
°
PhCO3 Bu as oxidant in DCE at 40 C using 2-methylanisole
(1 equiv.) and ethyl acrylate (1.5 equiv.) as model substrates
provided only traces amount of para olefinated product. To our
delight, using the modified S,O ligand L2, bearing a pentafluor-
obenzyl group attached to the sulfur atom, the yield improved
to 49% and a good site-selectivity towards the para olefinated
product (para:ortho:meta 8:1:1) was observed (see Supporting
Information Table S1). Subsequently, different solvents, temper-
atures and oxidants were evaluated (see Supporting Informa-
°
tion Table S2–S5). The reaction at 60 C provided an enhanced
yield of 80%, while retaining the site-selectivity. Next to DCE as
solvent, also acetic acid and ethyl acetate provided good
results.[11] When using HFIP and TFA as solvent, the product
coming from the double addition of anisole to ethyl acrylate
was observed (see Supporting Information, Scheme S1). With
the optimal reaction conditions in hand, 1 equiv, of anisole
derivative, 1.5 equiv. of ethyl acrylate, 10 mol% of Pd/L2
[a] Yields and selectivity were determined by 1H-NMR analysis of the crude
mixture using CH2Br2 as internal standard. Isolated yield is given in square
brackets: [total isolated yield, isolated yield of the major regioisomer]. [b]
t
°
catalyst, 1 equiv. of PhCO3 Bu in DCE at 60 C, we evaluated the
scope of substituted aryl ethers (Table 1).
The reaction of ortho-substituted anisoles bearing electron
donating groups (-Me 3a, -tBu 3b and -OMe 3c) provided the
olefinated products with good yields and site-selectivities in
favor to the para-product, which was isolated in synthetically
useful yields (>45%). We then focus our attention on the CÀ H
olefination of more challenging anisole derivatives bearing
electron withdrawing substituents. We found that under
optimal reaction conditions, the reaction of 2-fluoro-; 2-chloro-;
2-trifluoro-; and 2-methylester- anisole derivatives provided the
olefinated products in low yield (14–34%) with low site-
°
0.2 M DCE was used. [c] 0.4 M HFIP was used. [d] 0.2 M DCE at 80 C was
used. [e] 10.0 equiv. of anisole derivative and 1.0 equiv. of ethyl acrylate
were used. [f] Mono-olefinated product was isolated as a mixture of
regioisomers a:b 10:1. [g] Mono-olefinated product was isolated as a
mixture of regioisomers a:b 2.7:1. [h] 6% Z isomer was observed and the
isolated product was isolated with
a E/Z ratio of 8:1. n.d.=not
determined. w/o=without, DCE=1,2-Dichloroethane, HFIP=Hexafluoro-
2-propanol.
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Table 2. Scope of olefins.[a]
selectivities (see Supporting Information, Scheme S2). Further
optimization of the reaction conditions using 2-fluoroanisole
(1d) as model substrate revealed the use of HFIP as optimal
solvent,[12] furnishing the olefinated product 3d in 58% NMR
yield and with synthetically useful site-selectivity (para:ortho:
others 7.5:1.5:1). Under these conditions, the reaction of 2-Cl-
1e; 2-CF3-1g; and 2-CO2Me-1h anisole derivatives furnished the
desired products in good yields and site-selectivities, allowing
to isolate the para-olefinated products in a range of 50–66%
yield. Then, we evaluated 2-bromoanisole (1f) using HFIP as
solvent and we observed the formation of the olefinated
product in only 16% NMR yield and with low site-selectivity
(1.5:1) in favor to the para-product. We improved the NMR
°
yield to 48% by performing the reaction in DCE at 80 C.
However, under these conditions the site-selectivity remains the
same. To determine the effect of the substituent attached to
the oxygen atom, we performed the reaction of 2-methylbenzyl
tert-butyl ether (1i) in DCE, that proceeds with perfect site-
selectivity providing the desired the para-olefinated product in
52% isolated yield.
[a] Yields and selectivity were determined by 1H-NMR analysis of the crude
mixture using CH2Br2 as internal standard. Isolated yield of the ortho-
olefinated product is given in square brackets Trace amount of olefinated
product was detected for all substrates when the reactions were carried
out without ligand. [b] 0.2 M DCE was used. [c] 0.4 M HFIP was used. [d]
Di-olefinated product was observed in crude NMR (mono:di 5.5:1) and
isolated in 10% yield [e] Di-olefinated product was observed in crude
NMR (mono:di 19:1). n.d.=not determined. w/o=without, DCE=1,2-
Dichloroethane, HFIP=Hexafluoro-2-propanol.
Afterwards, we moved our attention to para-substituted
anisole derivatives (Table 1). The reaction of 4-methylanisole
°
(1j) in DCE at 60 C provided the olefinated products in 56%
isolated yield with good site-selectivity (9:1) in favor to the
ortho-olefinated product. We also observed the formation of
the di-olefinated product in a ratio 9 to 1 (mono/di). The
reaction of the more activated 4-methoxyanisole (1k) furnished
a 4 to 1 mixture of mono- and di-olefinated products in 78%
isolated yield, and the mono-olefinated product 3k was
obtained in 61% yield. When the reaction was performed using
anisole derivatives bearing electron withdrawing substituents
such as 4-F-; 4-CF3-; 4-CO2Me- and 4-NO2 (1l–1o), perfect site-
selectivity and only small amounts of di-olefinated products
were detected, allowing to isolate the ortho-products in
52%,69%, 69% and 82% yield, respectively.
To further prove the applicability of the new methodology
in the CÀ H olefination of anisole derivatives, we performed the
reaction using oxygen as the only oxidant (Scheme 2). The
reaction of 2-methyl anisole (1a) and ethyl acrylate using 1 bar
of oxygen showed the formation of 15% of olefinated product
3a. Fortunately, when using 3 bar of oxygen, the desired
product was obtained in 59% yield with good para selectivity,
highlighting the potential applicability of this methodology in
industry.[14]
In conclusion, we have developed a general methodology
for the CÀ H olefination of anisole derivatives by a Pd/S,O-ligand
catalyst. The reaction proceeds under mild conditions with a
broad range of aryl ethers bearing both electron donating and
withdrawing substituents at ortho, meta and para positions.
Aryl ethers are used as limiting reagents and good yields and
site-selectivities are observed. Additionally, a broad range of
activated olefins are successfully introduced. The methodology
is operationally simple and can be performed under aerobic
Finally, we also evaluated the CÀ H olefination of meta-
substituted anisole derivatives. The reaction of 3-OMe-; 3-Ph-;
and 3-CF3-anisole (1p–1r) under optimized conditions for each
substrate (DCE or HFIP) provided the olefinated products in
good yields with moderate to low site-selectivity in favor to the
less sterically hindered ortho-position. In addition, di-olefinated
products were also detected in the reaction of 3-OMe- and 3-
Ph-anisole (1p–1q).
Additionally, we performed the CÀ H olefination of sub-
stituted anisole derivatives in the absence of the L2. In all cases,
we observed the formation of traces amount of the olefinated
product or low yield when using HFIP as solvent, highlighting
the key role of the S,O-ligand L2 in the reaction. After proving
the efficiency of the new catalytic system on different
substituted anisole derivatives, we investigated the scope of
olefins as showed in Table 2. The reaction of 4-methylanisole
(1j) in DCM with methyl-, phenyl-acrylate and (methylsulfonyl)
ethene provided the ortho-olefinated products 4a, 4b and 4c
in good isolated yields (56–71%). 4-(Trifluoromethyl)anisole
(1m) was ortho olefinated with cyclohexyl acrylate (4d), 3-but-
2-one (4e) and dimethyl vinylphosphonate in good yields.[13]
Scheme 2. CÀ H Olefination of 2-methylanisole under aerobic conditions.
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Acknowledgements
We acknowledge financial support from NOW through an ECHO
grant (713.018.002).
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Conflict of Interest
The authors declare no conflict of interest.
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Keywords: Anisole · CÀ H activation · Olefination · Palladium ·
S,O-ligand
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Manuscript received: June 22, 2021
Revised manuscript received: July 19, 2021
Accepted manuscript online: July 20, 2021
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