Palladium-catalyzed oxidative heck coupling of cyclic enones with simple arenes by C-H activation

Article abstract of DOI:10.1002/cctc.201500079

A simple catalyst system consisting of Pd(OAc)₂ and 3-nitropyridine for the aerobic oxidative Heck coupling of cyclic enones, in particular challenging unsubstituted cyclic enones, with simple arenes by C-H activation was investigated. This novel method was applied to various functionalized arenes and cyclic enones and allowed the synthesis of β-aryl cyclic enones in modest to high yields.

Full text of DOI:10.1002/cctc.201500079

DOI: 10.1002/cctc.201500079
Communications
Palladium-Catalyzed Oxidative Heck Coupling of Cyclic
Enones with Simple Arenes by CÀH Activation
Leung Gulice Yiu Chung, Nur Asyikin Binte Juwaini, and Jayasree Seayad*[a]
A simple catalyst system consisting of Pd(OAc)2 and 3-nitropyr-
idine for the aerobic oxidative Heck coupling of cyclic enones,
in particular challenging unsubstituted cyclic enones, with
simple arenes by CÀH activation was investigated. This novel
method was applied to various functionalized arenes and
cyclic enones and allowed the synthesis of b-aryl cyclic enones
in modest to high yields.
(Scheme 1b) and oxidative Heck-type coupling by using aryl
boronic acids[7] (Scheme 1c) have been reported for the che-
moselective formation of aryl enones from the corresponding
enones. However, these methods still use functionalized cou-
pling partners and require the use of superstoichiometric
amounts of bases and complex ligands. Oxidative Heck cou-
pling[8] of cyclic enones with simple arenes by CÀH activation
eliminates the need for prefixing and subsequent removal of
the reactive functionalities and is intriguing in this context.
As part of our continued studies on the CÀH arylation of
arenes and heteroarenes,[9] we were interested in the coupling
of simple cyclic enones with arenes as an alternative strategy
towards functionalized biaryls. We developed and report
herein an operationally simple and efficient catalyst system
consisting of Pd(OAc)2 and 3-nitropyridine as the ligand for the
oxidative Heck coupling of cyclic enones with arenes
(Scheme 1d) by using molecular oxygen as the oxidant. In this
perspective, Hong et al.[10] recently reported an interesting se-
quential dehydrogenation–oxidative Heck coupling of chroma-
nones with arenes to form b-aryl chromenones by using a cata-
lyst system consisting of Pd(tfa)2 (tfa=trifluoroacetate) and
Cu(tfa)2 in the presence of AgOAc as the oxidant (Scheme 2a).
While we were preparing this manuscript, Gigant and Bäck-
C3-Arylated cyclic enones are important intermediates[1] in the
synthesis of pharmaceuticals, fine chemicals, and materials, in
particular as building blocks for chiral b-aryl ketones/amines,[2]
substituted phenols, and anilines.[3] They are commonly syn-
thesized by cross-coupling reactions of b-functionalized cyclic
enones with organometallic reagents.[4] The Heck arylation of
cyclic enones with aryl halides to form arylated enones
(Scheme 1a) is generally known to be challenging owing to
chemoselectivity issues resulting from a typical side reaction,
the conjugate addition reaction.[5] Alternatively, modified Heck-
type decarboxylative coupling by using aryl carboxylic acids[6]
Scheme 2. Dehydrogenative coupling of substituted cyclic ketones.
BQ=benzo-1,4-quinone.
vall[11] reported a sequential dehydrogenation–oxidative cou-
pling of cyclic saturated ketones with arenes in the presence
of molecular oxygen as the oxidant by using a catalyst system
consisting of Pd(OAc)2 together with electron-transfer media-
tors such as iron phthalocyanine and benzoquinone
(Scheme 2b). Unfortunately, this catalyst system was particular
to substituted cyclic ketones, and simple unsubstituted cyclic
ketones were found to decompose under the reaction condi-
tions. Our approach complements these methodologies and
allows the oxidative coupling of challenging unsubstituted
cyclic enones with simple arenes to form the corresponding b-
aryl cyclic enones.
Scheme 1. Heck-type b-arylation of cyclic enones. Ts = p-toluenesulfonyl.
[a] Dr. L. G. Y. Chung, N. A. B. Juwaini, Dr. J. Seayad
Organic Chemistry
Institute of Chemical and Engineering Sciences (ICES)
8 Biomedical Grove, Neuros #07-01, 138665 (Singapore)
E-mail: jayasree_seayad@ices.a-star.edu.sg
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201500079.
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In our preliminary experiments on the oxidative Heck cou-
pling of cyclohex-2-en-1-one (1a) with p-xylene (2a) as the
model substrates by using the reported procedure for the de-
hydrogenative coupling of chromanones,[10] we found that
only a trace amount of the coupled product 2’,5’-dimethyl-5,6-
dihydro-(1,1’-biphenyl)-3(4H)-one (3a; Table 1, entry 1) was
formed. However, the yield of the product as determined by
NMR spectroscopy increased to 17% if Pd(OAc)2/Cu(tfa)2/acetic
acid (AcOH) was used instead of Pd(tfa)2/Cu(tfa)2/pivalic acid
(PivOH) in the presence of AgOAc as the oxidant. A preliminary
examination of the solvents indicated that the reaction could
also be performed under neat conditions or in diglyme (up to
25% yield) in the presence of a small amount of acetic acid,
whereas other polar aprotic solvents such as DMF and DMSO
were unsuitable. Further varia-
tion of the oxidant showed no
Table 1. Optimization studies on the oxidative Heck coupling of cyclohex-2-en-1-one with p-xylene.
significant improvement in the
product yield. Prolonging the re-
action time was also not benefi-
cial, which indicated possible de-
activation of the catalyst after
the initial cycle. Formation of
a significant amount of Pd black
was also observed upon comple-
tion of the reaction. Conse-
quently, we examined various ni-
trogen ligands that are stable
under oxidative conditions to
stabilize the active palladium
species. In the presence of bi-
dentate ligands such as 1,10-
phenanthroline and 2,2’-bipyri-
dine, there was no reaction, pos-
sibly as a result of the formation
of inactive PdL2 complexes. Sub-
sequently, after examining vari-
ous monodentate pyridine li-
gands (Table 1, entries 5–12), we
were delighted to find a remark-
able increase in the yield upon
using pyridine ligands contain-
ing electron-withdrawing sub-
stituents, including 2-fluoropyri-
Entry
Catalyst
Ligand
Co-catalyst
Oxidant
Solvent
Yield
[%]
1
2
3
4
Pd(tfa)2
–
Cu(tfa)2
Cu(tfa)2
Cu(tfa)2
Cu(tfa)2
AgOAc
AgOAc
AgOAc
AgOAc
PivOH
AcOH
diglyme
–
trace
17
23
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
–
–
19
5
6
Pd(OAc)2
Pd(OAc)2
Cu(tfa)2
Cu(tfa)2
AgOAc
AgOAc
diglyme
diglyme
25
13
7
Pd(OAc)2
Cu(tfa)2
AgOAc
diglyme
13
8
9
Pd(OAc)2
Pd(OAc)2
Cu(tfa)2
Cu(tfa)2
AgOAc
AgOAc
diglyme
diglyme
54
68
10
11
12
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(tfa)2
Cu(tfa)2
Cu(tfa)2
AgOAc
AgOAc
AgOAc
diglyme
diglyme
diglyme
34
48
39
dine
(54%),
3-nitropyridine
(68%),
2,4-dichloropyridine
(38%), isonicotinonitrile (48%),
and 3-acetylpyridine (39%). In-
terestingly, weakly coordinating
pentafluoropyridine was not
useful. Unsubstituted pyridine or
pyridine with electron-donating
substituents such as 2,6-lutidine
and 3-methoxypyridine were
also not effective, which indicat-
ed the need for an electronically
and sterically balanced ligand for
good catalytic activity and stabil-
ity. Thus, further studies were
performed by using 3-nitropyri-
dine as the ligand. The reaction
was found to work equally well
with Ag2CO3 and more remarka-
bly by using molecular oxygen
(balloon) as the oxidant. Other
13
14
15
16
17
18
19
Pd(OAc)2
Pd(OAc)2
Pd(OPiv)2
Pd(tfa)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(tfa)2
Cu(tfa)2
Cu(tfa)2
Cu(tfa)2
Cu(OAc)2
Cu(OTf)2
–
Ag2CO3
O2
O2
O2
O2
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
69
68
52
45
25
15
75
O2
O2
20
Pd(OAc)2
–
O2
diglyme
trace
21
22
23
24
25
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
–
–
–
–
O2
O2
O2
O2
O2
DCE
80
66
trace[c]
trace[c]
37[d]
isopropyl acetate
MeTHF
DMC
DCE
[a] Reaction conditions: Cyclohex-2-en-1-one (1a, 0.5 mmol), p-xylene (15 mmol), catalyst (15–20 mol%), ligand
(30–40 mol%), co-catalyst (15–20 mol%), silver oxidant (1.5 equiv.), O2 (balloon), solvent (2 mL), AcOH (2 mmol),
1008C, 14 h. [b] Yield was determined by 1H NMR spectroscopy by using dibromomethane as an internal stan-
dard. [c] Formation of phenol was observed. [d] Reaction was performed at 808C.
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palladium precursors such as Pd(OPiv)2 and Pd(tfa)2 as well as
co-catalysts such as Cu(OAc)2 and Cu(OTf)2 (OTf=trifluorome-
thanesulfonate) were inferior. To our surprise, if the reaction
was performed without any copper co-catalyst, a better out-
come was obtained in that the coupled product was formed in
75% yield. Re-examination of the solvent under these condi-
tions revealed that the yield of the product was improved in
dichloroethane (DCE, 80%). Isopropyl acetate,[12] an environ-
mentally more friendly alternative, performed to some extent,
but the yield (66%) was not comparable to that obtained with
diglyme or DCE. Other solvents such as dimethyl carbonate
(DMC) and 2-methyltetrahydrofuran (MeTHF) were not suitable,
as reactions in these solvents mainly led to the dehydrogena-
tion of cyclohex-2-en-1-one to phenol. The optimum amount
of AcOH was found to be 4 equivalents with respect to the
enone. A ligand/palladium ratio of 2 was found to be optimal
for good catalytic activity (Figure S1, Supporting Information).
The concentration of the Pd catalyst also had a strong effect
on the reaction and 15–20 mol% Pd was found to be necessa-
ry to attain high yields (80–87%, Figure S2).
Table 2. Oxidative Heck coupling of simple cyclic enones with arenes.[a]
With the optimized conditions, we studied the scope of this
method for the coupling of different functionalized arenes and
cyclic enones (Table 2). In general, electron-rich arenes were
more reactive than their electron-poor counterparts, and the
respective coupled products were delivered in moderate to
high yields. Thus, the coupling of symmetric di- or trisubstitut-
ed arenes 2a–e with cyclohex-2-en-1-one (1a) gave coupled
products 3a–e in yields of 46–83%. For instance, p-xylene, 1,4-
dimethoxybenzene, and 1,3,5-trimethoxybenzene formed cou-
pled products 3a (80%), 3b (83%), and 3c (81%) in high
yields. Mesitylene formed 3d in 46% yield. Electron-poor 1,4-
dichlorobenzene also reacted under these conditions to form
3e in 57% yield.
As expected for unsymmetrically substituted arenes, the cor-
responding regioisomers were formed. For instance, as shown
in the Table 2, in the case of o-xylene the regioisomers of 3 f
were formed in a ratio of 1:0.7 in a total yield of 73%. In the
case of naphthalene, 3g was formed in 51% yield with a regioi-
someric ratio of 1:0.12. Similarly, 2,6-dimethylnaphthalene gave
product 3h (46%) as a regioisomeric mixture (1:0.26). In the
case of anisole, the corresponding ortho, meta, and para iso-
mers of 3i were formed in a total yield of 68% (o/m/p=
1:0.8:0.2). tert-Butylbenzene yielded a 1:1 ratio of the corre-
sponding meta/para isomers in a total yield of 60%. The ortho
isomer was not detected in this case, possibly because of
steric hindrance of the bulky tert-butyl group. Interestingly, the
reaction of 1,2-dimethoxy-4-methylbenzene proceeded well
and gave the corresponding isomers of 3k (1:0.5) in 57% yield.
Similarly 1-chloro-2-methylbenzene offered the corresponding
isomers of 3l (0.4:1). The method was also applicable to other
cyclic enones. For instance, cyclopent-2-en-1-one reacted with
p-xylene and 1,4-dimethoxybenzene to form coupled products
3n and 3o in yields of 66 and 71%, respectively. 4-Methylcy-
clohex-2-en-1-one reacted with p-xylene to give 2’,5’,6-trimeth-
yl-5,6-dihydro-(1,1’-biphenyl)-3(4H)-one (3m) in 40% yield. Un-
fortunately, these aerobic oxidative coupling conditions were
not suitable for fluorinated arenes, for which only trace
[a] Reaction conditions: Enone (0.5 mmol), arene (15 mmol), catalyst
(15 mol%), ligand (30 mol%), AcOH (2 mmol), DCE (2 mL), O2 (balloon),
1008C, 14 h. Yields of the isolated products are given. [b] Ag2CO3
(1.5 equiv.) was used as the oxidant in diglyme.
amounts of the coupled products were detected. Nevertheless,
Ag2CO3 was proven to be a good oxidant in these cases, and
fluorinated b-arylenones 3q–s were obtained in moderate to
high yields.
To understand the CÀH activation of the arenes, we studied
the kinetic isotope effect (KIE)[13] with respect to the arene. In-
terestingly, a very prominent primary KIE (kH/kD =7.7) was ob-
served in a competition reaction between p-xylene/[D10]p-
xylene (see the Supporting Information) and cyclohex-2-en-1-
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through Celite. The crude mixture
was analyzed by GC–MS and
1H NMR spectroscopy and was
then purified by flash column
chromatography (silica gel).
Acknowledgements
This project was funded by the
GlaxoSmithKline (GSK)–Singapore
partnership for green and sustain-
able manufacturing (GSM) and
the Institute of Chemical and En-
gineering Sciences.
Keywords: arenes
activation · cyclic enones · Heck
reaction · palladium
·
CÀH
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Experimental Section
In a glove box, a Radleys reaction tube was charged with Pd(OAc)2
(0.075 mmol), 3-nitropyridine (0.15 mmol), the arene (15 mmol),
AcOH (2 mmol), the cyclic enone (0.5 mmol), and the solvent
(2 mL). The tube was closed, removed from the glove box, and
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Received: January 27, 2015
Revised: February 23, 2015
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