S,O-ligand-promoted palladium-catalyzed C–H olefination of arenes with allylic substrates

Article abstract of DOI:10.1016/j.tetlet.2017.12.047

An efficient catalytic system for the C–H olefination of arenes with different allylic substrates is reported. The catalytic system is based on Pd(OAc)₂ and a readily accessible bidentate S,O-ligand. The methodology shows high activity with a wide range of arenes, including bulky and, electron-rich and -poor arenes. The applicability of this catalyst is demonstrated in the late-stage functionalization of the complex molecule O-methylestrone.

Full text of DOI:10.1016/j.tetlet.2017.12.047

Accepted Manuscript
S,O-Ligand-promoted palladium-catalyzed C−H olefination of arenes with al-
lylic substrates
Kananat Naksomboon, Yolanda Álvarez-Casao, Michiel Uiterweerd, Nick
Westerveld, Beatriz Maciá, M. Ángeles Fernández-Ibá ñez
PII:
S0040-4039(17)31550-2
https://doi.org/10.1016/j.tetlet.2017.12.047
TETL 49549
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 November 2017
10 December 2017
12 December 2017
Please cite this article as: Naksomboon, K., Álvarez-Casao, Y., Uiterweerd, M., Westerveld, N., Maciá, B.,
Fernández-Ibá ñez, M.A., S,O-Ligand-promoted palladium-catalyzed C−H olefination of arenes with allylic
substrates, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.12.047
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S,O-Ligand-promoted palladium-catalyzed
CH olefination of arenes with allylic
substrates
Leave this area blank for abstract info.
Kananat Naksomboon, Yolanda Álvarez-Casao, Michiel Uiterweerd, Nick Westerveld, Beatriz Maciá and M.
Ángeles Fernández-Ibáñez*

1
Tetrahedron Letters
S,O-Ligand-promoted palladium-catalyzed CH olefination of arenes with allylic
substrates
Kananat Naksomboona, Yolanda Álvarez-Casaoa, Michiel Uiterweerda, Nick Westervelda, Beatriz Maciáb
and M. Ángeles Fernández-Ibáñeza,
a Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands.
b Division of Chemistry & Environmental Science, Manchester Metropolitan University, Oxford Road, M1 5GD, Manchester, UK.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient catalytic system for the CH olefination of arenes with different allylic substrates is
reported. The catalytic system is based on Pd(OAc)2 and a readily accessible bidentate S,O-
ligand. The methodology shows high activity with a wide range of arenes, including bulky and,
electron-rich and -poor arenes. The applicability of this catalyst is demonstrated in the late-stage
functionalization of the complex molecule O-methylestrone.
Available online
Keywords:
CH activation
S,O-ligand
palladium
allylation
2009 Elsevier Ltd. All rights reserved.
arenes
In recent years, metal-catalyzed CH functionalization
reactions have become an attractive strategy to introduce
complexity to organic molecules since no pre-functionalization of
the starting materials is required.1 Many elegant and efficient
methodologies have been described for the direct
functionalization of CH bonds, but the vast majority of these
examples require the presence of a directing group to enhance the
reactivity and selectivity of the process.2 Reports of the direct
CH functionalization of simple arenes, without a directing
group, are still scarce.3 An attractive alternative to the use of
directing groups is the use of suitable ligands capable of
promoting these transformations.4 We recently reported a new
type of bidentate S,O-ligand, namely 2-i-propyl-2-
(phenylthio)acetic acid (L1), that enables the non-directed Pd-
catalyzed CH olefination5 of arenes with activated olefins.6 The
methodology is scalable and applicable to the late-stage
functionalization of complex molecules. Although our standard
reaction conditions (Pd(OAc)2/L1; PhCO3tBu; AcOH) provided
poor yields and did not accelerate the reaction with non-activated
alkenes, the use of AgOAc in DCE was observed to have a
beneficial effect in promoting the olefination of benzene with
allylbenzene when L1 was present in the reaction mixture
(Scheme 1).7
Scheme 1. S,O-Ligand promoted CH olefination of benzene.
palladium(II)-catalyzed CH olefination of arenes with allylic
substrates. The new methodology is suitable for a wide range of
arenes and allylic substrates and its applicability is demonstrated
in the late-stage functionalization of a complex molecule.
We started our investigation optimizing the reaction
conditions by testing several solvents, oxidants and palladium
sources (see ESI for further details). However, no improvement
was observed in comparison with the original conditions (10
mol% Pd(OAc)2, 10 mol% L1, 1.5 equiv. AgOAc, DCE, 80 °C).
With the optimized conditions in hand, we then explored the
scope of the reaction with respect to the arene and allyl partners
(Table 1). The reaction of naphthalene with allylbenzene
provided the desired allylated products 2 in high yield (89%)
(Entry 1). Similarly, the reaction with o-xylene and anisole
furnished the allylated products 3 and 4 in good isolated yields,
62% and 68%, respectively (Entries 2 and 3). We also
Inspired by this preliminary result, we decided to explore the
scope of the new catalytic system in the CH olefination of
arenes with allylic substrates, including allyl acetate and N-
allylphthalimide. Herein, we report the S,O-ligand promoted
———
 Corresponding author. Tel.: +31-2052-5873; e-mail: M.A.FernandezIbanez@uva.nl

Table 1. Scope of the L1-promoted palladium-catalyzed CH olefination with allyl substrates.
2
Tetrahedron
Entry
1
Product
Yield (%)a with L1
α/β or o/m/p (%)c
a/a’ or b/b’ or c/c’ (%)c
E/Z (%)c
Yield (%)a or b without L1
e
2a/a’
3a/a’
89
50a
64/36d
42/58d
62
37a
38/62d
50/50d
65/35d
e
f
2
3
4a/a’
68
62/4/34d
37a
4
5b/b’
65
-
92/8
90/10
36b
f
f
f
5
6
7
6b/b’
75
55b
60/40g
95/5
91/9
85/15
7b/b’
74
38b
36/64
8b/b
’
53
13/65/22 (o/o’/m)
36b
8
9
9b/b’
67
12b
-
71/29
93/7
86/14
f
10b/b’
78
68/0/32g
38b
e
10
11
11b/b’
82
30a
17/83
91/9
88
-
94/6d
95/5d
47b
12b/b’
12
13b/b’ 40
-
62/38
69/31
25b
13
14
14c/c’
73
20b
-
-
71/29
98/2
93/7
f
61
36b
15c/c’
Reagents and conditions: arene (33 or 66 equiv.), olefin (1.0 equiv.), Pd(OAc)2/S,O-Ligand (10 mol%), AgOAc (1.5 equiv.), DCE, 80-100 C, 20-24 h.
aIsolated yield. bCalculated yield based on 1H-NMR yield using dibromomethane as an internal standard. cDetermined by 1H-NMR analysis of the isolated
mixture. dDetermined by GC analysis. eNo Z isomer detected. fTraces of Z isomer detected. gRatio measured from the b isomer.

3
studied the generality of this reaction using other allylic
substrates such as allyl acetate and N-allylphthalimide. These
allyl substrates have been scarcely used in coupling reactions due
to the low selectivities regarding the Pd insertion (internal vs
terminal) and the β elimination (β-H vs β-OAc or β-NPhth and
styrenyl vs allylic).8 Using our method, the reaction of allyl
acetate with benzene, naphthalene or arenes with alkyl
62/38 for 1,3,5-trifluorobenzene; Entries 8, 12 and 13,
respectively). In addition, some isomerization of double bond to
the Z isomer occurred in the reaction of these arenes with allyl
acetate (Entries 8 and 12). The low regioselectivity observed can
be explained by the steric hindrance of the arene, which hampers
rotation around the C-C bond, disfavouring the syn relationship
between the Pd and Hb.10
substituents, such as o-xylene, m-xylene and mesitylene,
provided the desired allylated products in good isolated yields
(53-75%, Entries 4-8). Other arenes with different electronic
properties, such as anisole, 4-chloroanisole, 4-methoxyanisole
and 1,3,5-triflurobenzene were also evaluated in the reaction with
allyl acetate. In all cases, the allylated products were obtained in
good isolated yields (40-88%, Entries 9-12). In addition, we
tested the reaction of N-allylphthalimide with mesitylene and
1,3,5-trimethoxybenzene. In both cases, the allylated products
were isolated in good yields (73% and 61%, respectively, Entries
13-14). Importantly, in all cases, the reaction was accelerated in
the presence of L1 and low yields were obtained without the
ligand after 20-24 h (Table 1, Entries 1-14). It is worth
To further prove the generality of the new catalytic system, we
applied the new developed methodology to the late-stage
functionalization of a complex molecule (Scheme 3). The
reaction of O-methylestrone (1 equiv.) with allyl acetate (1.5
equiv.) and Pd(OAc)2 (10 mol%) provided the desired product in
only 10% 1H-NMR yield. To our delight, the same reaction in the
presence of L1, furnished the olefinated product 16 in 55%
isolated yield as a mixture of ortho-olefinated isomers (a:b =
60:40).
highlighting the effect of the ligand L1 in the reactivity with the
bulky mesitylene. The reaction of mesitylene with allyl acetate or
N-allylphtalamide in the absence of L1 proceeded with
conversions lower than 20%. In contrast, the allylated products 9
and 14 were obtained in 67% and 73% isolated yield,
respectively, in the presence of L1 (Entries 8 and 13). In general,
the new catalytic system promoted the allylation of a wide
variety of arenes including bulky, electron-rich and electron-poor
arenes, providing a broader substrate scope than the majority of
the reported examples.7-9 With respect to other arenes, we found
that the reaction of different dichlorobenzene derivatives
provided the corresponding allylated products in low yields, with
and without L1. Regarding the site-selectivity of the process, the
allylation reaction takes place, preferentially, at the most
electron-rich position in the arene (see α/β or o/m/p values in
Table 1). Similar behaviour was observed in our previous work
using activated olefins.6
Scheme 3. Late-stage CH olefination of Estrone.
In summary, the combination of Pd(OAc)2 and the bidentate
S,O-ligand L1, was found to promote the C-H olefination of
arenes with different allyl substrates, providing the desired
allylated products in good yields. This transformation tolerates a
wide range of arenes, including bulky, electron-rich and electron-
poor arenes. The olefination reaction occurs preferentially at the
most electron-rich position of the arene. Regarding the
regioselectivity of the β-hydride elimination, mixtures of isomers
were obtained in the reaction with allyl benzene and mainly one
isomer in the reaction with allyl acetate and N-allylphtalamide;
these results are in line with the general outcome of the Heck
reaction. The applicability of the new catalytic system has been
demonstrated in the late-stage functionalization of O-
methylestrone.
Concerning the selectivity of β-hydride elimination in the
reaction with allylbenzene, a c.a. 1:1 mixture of isomers was
observed (Entries 1-3).9 For the olefination reactions with allyl
acetate or N-allylphthalimide, more complex mixtures of
products can be formed.8 However, in all of the examples
evaluated, we observed only the products from internal
carbopalladation (Entries 4-14). After the carbopalladation step,
β-OAc [or β-(NPhth)] elimination or β-hydride elimination can
take place. However, under our reaction conditions, we did not
detect the products derived from β-OAc [or β-(NPhth)]
Acknowledgments
elimination. Furthermore, with respect to the β-hydride
We acknowledge financial support from NWO through a
VIDI grant (723.013.006). We acknowledge Simone Sozzi for
the synthesis of some reference compounds. B.M. and M.A.F.I.
thank the R.S. for a travel grant.
elimination pathway, although two possible products can be
formed, we observed mainly the products from the β-hydride
elimination that leads to the double bond in conjugation with the
arene. This high regioselectivity has been previously attributed to
chelation between the O and the Pd atom.7,8a-b This chelation
impedes rotation around the C-C bond and therefore, hinders the
syn relationship between the Pd and Ha (Scheme 2). To this
general trend, we found that the reaction with mesitylene and
1,3,5-trifluorobenzene afforded the allylated products 9, 13 and
14 with moderate regioselectivity (71/29 for mesitylene and
Notes
The authors declare no competing financial interest.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at…
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Scheme 2. Source of the high observed regioselectivity.

4
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5
Highlights
-
-
-
A new catalytic system for the C-H allylation of
arenes is presented.
The reaction tolerates a wide number of arenes
and allylic substrates
Late-stage functionalization of a complex
molecule is reported