Controlling reactivity in the Fujiwara–Moritani reaction: Examining solvent effects and the addition of 1,3-dicarbonyl ligands on the oxidative coupling of electron rich arenes and acrylates

Article abstract of DOI:10.1016/j.tetlet.2019.151471

A palladium-catalysed direct alkenation of electron rich arenes in the presence of K₂S₂O₈ with an acetic acid/1,4-dioxane solvent combination has been developed. The 1,4-dioxane co-solvent dramatically influences the rate of reaction, giving selectively disubstituted alkenes, while the addition of acetylacetone ligands was shown to increase site selectivity for the alkenation of monofunctionalized arenes. The participation of these carbonyl ligands has been confirmed by ESI-MS studies, with some key in situ intermediates in the catalytic cycle identified. A variety of electron rich arenes and olefinic substrates can be utilised in the direct oxidative coupling to give disubstituted alkenes in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2019.151471

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Controlling reactivity in the Fujiwara–Moritani reaction: Examining
solvent effects and the addition of 1,3-dicarbonyl ligands on the
oxidative coupling of electron rich arenes and acrylates
Roderick C. Jones
School of Chemical & Bioprocess Engineering University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalysed direct alkenation of electron rich arenes in the presence of K2S2O8 with an acetic
acid/1,4-dioxane solvent combination has been developed. The 1,4-dioxane co-solvent dramatically influ-
ences the rate of reaction, giving selectively disubstituted alkenes, while the addition of acetylacetone
ligands was shown to increase site selectivity for the alkenation of monofunctionalized arenes. The par-
ticipation of these carbonyl ligands has been confirmed by ESI-MS studies, with some key in situ interme-
diates in the catalytic cycle identified. A variety of electron rich arenes and olefinic substrates can be
utilised in the direct oxidative coupling to give disubstituted alkenes in moderate to good yields.
Ó 2019 Elsevier Ltd. All rights reserved.
Received 1 October 2019
Revised 28 November 2019
Accepted 29 November 2019
Available online xxxx
Keywords:
Olefination
CAH activation
Electron rich arenes
Fujiwara–Moritani reaction
In the case of alkene derivatization, the Fujiwara–Moritani (F-
M), or dehydrogenative Heck reaction, has become a popular trans-
formation in the modern class of CAH functionalization reactions
[1]. First developed by Fujiwara and co-workers, this methodology
showed both olefinic and aromatic bonds could be activated in
acetic acid with a stoichiometric, and later, catalytic amount of pal-
ladium to give alkenylated aromatic compounds [2]. Although
extensively explored for the conversion of monosubstituted alke-
nes, such as acrylates into disubstituted products [3], little study
has been conducted on developing a general methodology for con-
trolling ‘‘over reactivity”. A typical reaction outcome observed in
systems where both olefin and arene are electron rich. In this case,
yields of the desired disubstituted products are reduced by the for-
mation of trisubstituted alkenes; a competitive process typically
controlled by reaction time, increased arene concentration, or
directing groups [3b,3e,3–4].
Of late, our research focus has been the development of novel
strategies for the synthesis of tri- and tetrasubstituted alkenes
[5]. More recently we have developed a general and efficient F-M
protocol for the direct arene-1,2-disubstituted alkene couplings
to generate trisubstituted alkenes [6]. In this study the reaction
solvent mixture (AcOH/MeCN) and the use of a relatively insoluble
inorganic oxidant (K2S2O8) were key to achieving positive reaction
outcomes. In this report we have built upon our earlier findings
and describe our effort toward a general set of reaction conditions,
for the direct arylation of electron rich monosubstituted alkenes
using a Pd-catalysed oxidative coupling approach.
It was considered that the problem of ‘‘over reactivity”, so typ-
ically observed in the formation of electron rich disubstituted alke-
nes, could be controlled by the appropriate choice of solvent
system. Computational studies of CAH activation reactions have
shown that solvent molecules coordinating the active metal center
can lower the energetics of key intermediates, control the speed of
product release and directly affect the yield [7]. In our previous
research [6] we demonstrated a dramatic accelerating or decelerat-
ing effect in the synthesis of trisubstituted alkenes with the addi-
tion of a co-solvent; MeCN or 1,4-dioxane. ESI-MS of in situ
intermediates identified several key organopalladium species
expected for a F-M catalytic cycle containing MeCN solvent mole-
cules. With this in mind, our optimization strategy was to use pre-
viously developed conditions for the synthesis of tri-substituted
alkenes; Pd(OAc)2 as a palladium source, K2S2O8 as an inexpensive
and relatively insoluble inorganic oxidant and AcOH/MeCN (4:1) as
a solvent system at 80 °C.
The coupling of ethylacrylate 1a and 1,4-dimethoxybenzene 2a
were tested in a preliminary reaction utilizing 5 mol% of Pd(OAc)2
and a 7.5-fold excess of arene in AcOH/MeCN (4:1) for 24 h at 80 °C
(Table 1, entry 1) [8]. To our surprise, the sole reaction product was
the undesired trisubstituted alkene 4a, in 78% yield. In order to
limit the unwanted 2nd arene addition, the reaction time was
shortened to 1.5 h [9] giving the desired product 3a in 37% yield
(entry 2). Variation of the arene under these reaction conditions
E-mail address: roderick.jones@ucd.ie
https://doi.org/10.1016/j.tetlet.2019.151471
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: R. C. Jones, Controlling reactivity in the Fujiwara–Moritani reaction: Examining solvent effects and the addition of 1,3-dicarbonyl
ligands on the oxidative coupling of electron rich arenes and acrylates, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151471

2
R.C. Jones / Tetrahedron Letters xxx (xxxx) xxx
Table 1
Optimization of the reaction conditions.a
Entry
1
2
Co-solvent
R
Ar
Oxidant
Time (h)
3
Yield(%)b
4
Yield (%)b
1
2
3
4
5
6
7
8
a
a
a
a
b
b
b
b
b
b
b
b
b
a
a
b
c
a
a
b
c
a
b
c
a
a
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Et
Et
Et
Et
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
1,4-(MeO)2C6H3
1,4-(MeO)2C6H3
MeOC6H4
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
(Bu4N)2S2O8
(NH2)2S2O8
24
a
a
b
c
d
d
e
f
d
e
f
d
d
–
a
a
b
c
d
d
e
f
d
e
f
d
d
78
–
–
–
74
–
–
–
–
–
1.5d
1.5d
1.5d
24
37
43c
21
–
44
52c
32
71
63c
48
<5
<5
Ph
1,4-(MeO)2C6H3
1,4-(MeO)2C6H3
MeOC6H4
3d
3d
Ph
3d
9
1,4-(MeO)2C6H3
MeOC6H4
Ph
1,4-(MeO)2C6H3
1,4-(MeO)2C6H3
24
24
24
24
10
11
12
13
–
–
–
24
a
b
c
Reagents and conditions: 2 mmol of alkene, 15 mmol of arene, 5 mol% Pd(OAc)2, 4 mmol K2S2O8, AcOH/co-solvent (4:1).
Isolated yield after chromatography.
Product isolated as a series of isomers, o:m:p.
d
Longest possible reaction time before detection of the undesired trisubstituted alkene (as determined by GC) [9].
gave yields of 43% for 3b and 21% for 3c using anisole and benzene,
respectively (entries 3, 4).
and 13), the alkene was consumed but little to no coupling
products were detected. This can be attributed to the competing
oxidation of the starting material by the strong highly soluble
oxidants.
In order to minimize suspected alkene polymerization and
increase the product yield, the more stable butylacrylate was tri-
alled as a suitable alkene substrate. At 24 h (entry 5) the sole pro-
duct, 4d was isolated in 74% yield, comparable to that of 4a.
Shortened reaction times [9] gave the disubstituted alkenes 3d,
3e and 3f in 44%, 52% and 32% yields, respectively (entries 6–8).
The addition of 1,4-dioxane has previously been shown to dramat-
ically slow the rate of alkene conversion and minimize palladium
mediated alkene polymerization [6]. Computational studies of sol-
vent effects in CAH activation reactions support this and show that
dioxane can have a direct influence on reaction outcomes; by coor-
dinating to the Pd metal center when required and helping the pro-
duct separation from the Pd ligand field [7d]. In our case, use of
1,4-dioxane as a co-solvent (entries 9–11), indeed slowed the
rate of alkene conversion and polymerization giving a 71% yield
for 3d with no diarylated product detected in 24 h. It was
observed in successive experiments with anisole and benzene,
comparable yields of the desired alkenes 3e and 3f could be
achieved (63% and 48% respectively; entries 10 and 11), with no
trisubstituted products detected. When the organic soluble
oxidant variants tetrabutylammonium persulfate (Bu4N)2S2O8
and ammonium persulfate (NH4)2S2O8 were utilized (entries 12
Next, using 1,4-dimethoxybenzene as an electron rich arene,
the four alkenes ethylacrylate, butylacrylate, phenylvinyl sulfone
and acrylic acid (Table 2, entries 1–4), were examined for their
ability to undergo F-M coupling under our developed conditions.
In each case the reaction was successful, with disubstituted alke-
nes (3a, d, g and h) isolated in good to moderate yields of 65%,
71%, 61% and 51%, respectively. As expected, butylacrylate 1b
was the most reactive of the alkenes and acrylic acid 1d the least.
In all cases no doubly substituted product was observed in the 24 h
reaction period.
It was hoped that our reaction conditions would be suitable for
the introduction of 1,3-dicarbonyl compounds as ligands. Known
for their use in Cu-catalyzed processes [10] and as metal stabiliza-
tion reagents [11], they have had limited application in Pd-cat-
alyzed transformations [12] and may act as alternatives for the
typical pyridine [3b,3i,13] or amino acid based ligands [14] used
in the F-M reaction. The reaction of butylacrylate 1b and anisole
2d in the developed conditions gave the coupling product 3e in
63% yield with a ortho:meta:para ratio of 40:0:60 (Table 3, entry
1) using Pd(OAc)2 as a catalyst.
Table 2
Alkene coupling with 1,4-dimethoxybenzene.a
Entry
1
Alkene (R)
Time (h)
3
Yield (%)b
1
2
3
4
a
b
c
C(@O)OEt
C(@O)OBu
SO2Ph
24
24
24
24
a
d
g
h
65
71
61
51
d
C(@O)OH
a
Reagents and conditions: 2 mmol of alkene, 15 mmol of 2a, 5 mol% Pd(OAc)2, 4 mmol K2S2O8 AcOH/1,4-dioxane (4:1).
Isolated yield after chromatography.
b
Please cite this article as: R. C. Jones, Controlling reactivity in the Fujiwara–Moritani reaction: Examining solvent effects and the addition of 1,3-dicarbonyl
ligands on the oxidative coupling of electron rich arenes and acrylates, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151471

R.C. Jones / Tetrahedron Letters xxx (xxxx) xxx
3
Table 3
Coupling of various acrylates and electron rich arenes using different catalysts and solvents to control the regioselectivity.a
Entry
Solvent
Catalyst
2
Ar
Additiveb
Selectivityc
Time (h)
3
Yield (%)d
1
2
3
4
5
6
7
8
AcOH/1,4-dioxane
AcOH/1,4-dioxane
AcOH/1,4-dioxane
AcOH/1,4-dioxane
AcOH/1,4-dioxane
AcOH
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
Pd(acac)2
d
d
d
d
d
d
d
d
d
e
e
e
e
f
MeOC6H4
MeOC6H4
MeOC6H4
MeOC6H4
MeOC6H4
MeOC6H4
MeOC6H4
MeOC6H4
–
acac
40, –, 60
19, 13, 68
50, –, 50
15, 22, 63
20, 12, 68
19, 10, 71
44, –, 56
24, 21, 55
–
14, 86
10, 90
12, 88
5, 95
24
24
24
24
24
24
3
24
24
24
3
e
e
e
e
e
e
e
e
e
i
63
55
53
51
60
33
56e
68
<5
19
45e
50
65
41
hfacac
tBuacac
–
–
–
AcOH/MeCN
AcOH/1,4-dioxane
AcOH/1,4-dioxane
AcOH
120 °C
NaOAc
9
MeOC6H4
10
11
12
13
14
1,2-(MeO)2C6H3
1,2-(MeO)2C6H3
1,2-(MeO)2C6H3
1,2-(MeO)2C6H3
1,3-(MeO)2C6H3
–
–
–
–
–
AcOH/MeCN
i
i
i
j
AcOH/1,4-dioxane
AcOH/1,4-dioxane
AcOH/1,4-dioxane
24
24
24
–
a
b
c
Reagents and conditions: 2 mmol of alkene, 15 mmol of arene, 5 mol% Pd(OAc)2, 4 mmol K2S2O8, AcOH/co-solvent (4:1).
25 mol% of ligand were added per Pd. For entry 9, 10 mol% of NaOAc was added.
o:m:p selectivity ratio determined from crude 1H NMR and GC.
Isolated yield after chromatography.
Reaction time was shortened to 3 h, to eliminate the formation of trisubstituted alkene (as determined by GC) [9].
d
e
When the 1,3-dicarbonyl compounds, acetylacetone (acac),
Electrospray ionization mass spectrometry (ESI-MS), is an
invaluable tool for the detection of short-lived species during cat-
alytic processes [16]. To elucidate the role of acac as a ligand under
our reaction conditions, butylacrylate 1b and 1,4-dimethoxyben-
zene 2a were used as substrates and the reaction was monitored
by MS. ESI(+)-MS analysis was carried out on two key reagent com-
positions: (i) Pd(acac)2 in AcOH/1,4-dioxane and (ii) Pd(acac)2 in
AcOH/1,4-dioxane with 1b, 2a and K2S2O8 under the standard reac-
tion conditions. In each case the MS analysis showed intermediates
consistent with acac having an active role in the F-M catalytic cycle
(ESI, Figs. 1, 2).
Analysis of the composition (i) showed two main Pd isotopic
clusters centered at m/z 327.2 and 632.8. The most abundant clus-
ter centered at m/z 327.2 is consistent with a sodium adduct of
acac bound monomeric palladium species [Pd(acac)2 + Na]+, while
the mass at 632.8 being that of the palladium dimer, [Pd2(acac)4 +-
Na]+. This gives evidence of the predominance of monomeric Pd
(acac)2 in the AcOH/1,4-dioxane solvent mixture unlike Pd(OAc)2
which tends to exist as a trimer in acidic solvent mixtures without
the presence of strongly coordinating solvent such as MeCN [6,17].
With a key monomeric palladium species identified, the MS
analysis of mixture (ii) (generated following the addition of 1,4-
dimethoxybenzene (2a) butyl acrylate (1b) and K2S2O8 to a solu-
tion of AcOH/1,4-dioxane and subsequent heating at 80 °C for
1 h), gave rise to a series of identifiable species consistent with
the CAH insertion step of the F-M reaction (Fig. 1). The most abun-
dant new cluster was observed at m/z 342.9 and is consistent with
2a CAH inserted into the Pd species [Pd(acac)(C8H9O2)]+ (Fig. 1(b)).
Two more clusters of interest are observed at m/z 469.4 and 508.6.
Provisionally, they can be attributed to the palladium/product
complex, [Pd(acac)(C15H19O4)]+ (Fig. 1(a)) and the dimeric arene
coupled dimer containing an acetic acid molecule, [Pd2(OAc)
(acac)(C8H9O2)]+. Overall this study confirms that when utilized,
acac, not 1,4-dioxane, is acting as a ligand in our F-M reaction
conditions.
hexafluoroacetylacetone (hfacac) and 2,2,6,6-tetramethyl-3,5-hep-
tanedione (tBuacac) were utilized as ligands (entries 2–4) a shift in
t
product selectivity was detected. In the case of acac and Buacac a
decrease in ortho and an increase in meta product formation was
observed with comparable yields (55% and 51%, respectively). In
the case of hfacac (entry 3), a 50:50 mix of ortho:para isomers in
addition to palladium mirror formation (indicating catalyst degra-
dation, not previously detected) was observed. When the pre-
formed catalyst Pd(acac)2 was added to the reaction (entry 5) a
comparable yield and product selectivity was observed for 3e indi-
cating that the ligand coordinates to the Pd center and remains
present throughout the reaction time period of 24 h. If the alterna-
tive solvent systems of AcOH and AcOH/MeCN are used with Pd
(acac)2 (entries 6, 7) a comparable selectivity is achieved with
AcOH (with a lower yield for 3e, 33%) but for the AcOH/MeCN sol-
vent system a switch in selectivity of 44:56, ortho:para is detected.
This indicates MeCN is a stronger ligand than acac and can outcom-
pete when used as a solvent. If the reaction temperature is
increased (entry 8), a slight increase in yield and formation of
the meta isomer is achieved for 3e when compared to entry 5. If
NaOAc is added to increase the rate of product release from the
Pd centre [15], little to no product is formed with large amounts
of acrylate decomposition products detected (entry 9). In order to
show that this shift in product regioselectivity was possible for
another electron rich arene, the coupling of butylacrylate 1b and
1,2-dimethoxybezene 2e was examined (entries 10–13). In AcOH,
Pd(OAc)2 gave product 3i in a very low yield of 19% with a regios-
electivity of 14:86 ortho:para (entry 10). Using MeCN as a co-sol-
vent with Pd(OAc)2 (entry 11) 3i was formed in 44% yield with
an ortho:para selectivity of 10:90. Exchanging 1,4-dioxane for
MeCN (entry 12) results in a comparable yield and selectivity of
3 g. If Pd(acac)2 is utilized as the catalyst (entry 13) a higher yield
of 3i can be obtained and a shift in isomer formation to 5:95 is
detected giving the expected shift to the favoured para isomer as
observed for anisole. In the case of 1b and 1,3-dimethoxybenzene
2f (entry 14) the desired compound 3j was formed as one isomer in
low yield (41%).
In conclusion, we have developed an efficient protocol for the
direct electron rich arylation of acrylates to generate electron rich
disubstituted alkenes. The use of AcOH/1,4-dioxane and the
Please cite this article as: R. C. Jones, Controlling reactivity in the Fujiwara–Moritani reaction: Examining solvent effects and the addition of 1,3-dicarbonyl
ligands on the oxidative coupling of electron rich arenes and acrylates, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151471

4
R.C. Jones / Tetrahedron Letters xxx (xxxx) xxx
Appendix A. Supplementary data
(a)
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151471.
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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Acknowledgments
Some of this work was financially supported by the Irish
Research Council (IRC) (EMPOWER post-doctoral fellowship
PD/2011/2132). Additionally, the author would like to thank the
School of Chemical & Bioprocess Engineering University College
Dublin (UCD) for their support in the writing of this article.
[8] Typical coupling procedure: Pd(OAc)2 (22 mg, 5 mol%), K2S2O8 (0.81 g, 3
mmol), alkene (2 mmol), arene (15 mmol, 7.5 equiv), acetic acid (8 mL) and
cosolvent (2 mL) were placed in
a 20 mL scintillation vial containing a
magnetic stirrer bar. The flask was sealed with a Teflon-lined crimped cap, and
the reaction solution was stirred vigorously at 80 °C for 24 h (unless otherwise
Please cite this article as: R. C. Jones, Controlling reactivity in the Fujiwara–Moritani reaction: Examining solvent effects and the addition of 1,3-dicarbonyl
ligands on the oxidative coupling of electron rich arenes and acrylates, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151471

R.C. Jones / Tetrahedron Letters xxx (xxxx) xxx
5
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vacuo, and the residue purified by column chromatography on silica gel.
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trisubstituted alkene formation would act as a competing process to the
formation of the desired disubstituted alkene. Consequently, the reaction was
stopped before any trisubstituted alkene was observed (i.e. double addition of
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Please cite this article as: R. C. Jones, Controlling reactivity in the Fujiwara–Moritani reaction: Examining solvent effects and the addition of 1,3-dicarbonyl
ligands on the oxidative coupling of electron rich arenes and acrylates, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151471