Heck-Matsuda reactions catalyzed by a hydroxyalkyl-functionalized NHC and palladium acetate

Article abstract of DOI:10.1002/ejoc.201200181

The functionalized NHC obtained from salt 2 is a good ligand for palladium in the Heck-Matsuda reaction of arenediazonium salts and different alkenes. The reaction is performed with low catalyst loading (0.5-1 mol-% of Pd) and in the absence of a base for acrylates. The protocol is also useful for the preparation of cinnamide derivatives. Compound U-77863 has been prepared successfully in good isolated yield. Cyclohexene was found to be an appropriate substrate for the reaction, giving the corresponding 1-arylcyclohexene as a single regioisomer under the studied reaction conditions. The optimal parameters of the reaction were studied by employing a design of experiments approach. Thus, the use of a small set of reactions allows the trends of the different factors to be studied. This study revealed that the best catalytic system is formed by combination of Pd(OAc)₂ and salt 2 in a 1:2 ratio. This catalytic system produces better results without the use of a base. Copyright

Full text of DOI:10.1002/ejoc.201200181

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FULL PAPER
DOI: 10.1002/ejoc.201200181
Heck–Matsuda Reactions Catalyzed by a Hydroxyalkyl-Functionalized NHC
and Palladium Acetate
Itziar Peñafiel,[a] Isidro M. Pastor,*[a] and Miguel Yus*[a]
Dedicated to the memory of Balbino Mancheño
Keywords: Carbene ligands / Palladium / Alkenes / Nitrogen heterocycles
The functionalized NHC obtained from salt 2 is a good ligand
a single regioisomer under the studied reaction conditions.
for palladium in the Heck–Matsuda reaction of arenediazon- The optimal parameters of the reaction were studied by em-
ium salts and different alkenes. The reaction is performed
with low catalyst loading (0.5–1 mol-% of Pd) and in the ab-
sence of a base for acrylates. The protocol is also useful for
the preparation of cinnamide derivatives. Compound U-
77863 has been prepared successfully in good isolated yield.
Cyclohexene was found to be an appropriate substrate for
the reaction, giving the corresponding 1-arylcyclohexene as
ploying a design of experiments approach. Thus, the use of
a small set of reactions allows the trends of the different fac-
tors to be studied. This study revealed that the best catalytic
system is formed by combination of Pd(OAc)2 and salt 2 in a
1:2 ratio. This catalytic system produces better results with-
out the use of a base.
(Scheme 1).[11] Although NHC-Pd complexes exhibit sig-
nificant stability, they have not been considered in many
palladium-catalyzed transformations.[12]
Introduction
N-heterocyclic carbenes (NHCs), which constitute the
largest and most important group of stable aminocarb-
enes,[1] are frequently the center of attention due to their
use both as ligands in transition-metal catalysis and as or-
ganocatalysts. NHCs are indeed strong σ-donor and weak
π-acceptor ligands,[2] which make Pd0 complexes more elec-
tron rich. Moreover, functionalized NHCs are a new type
of ligand that are able to modulate their catalytic activities
in different processes.[3] Imidazolium salts, which are usu-
ally employed in the formation of NHC ligands, can be pre-
pared with a variety of functionalities.[4–8] Among them, hy-
droxy-functionalized imidazolium derivatives can be
straightforwardly prepared by ring opening of epoxides
with imidazole followed by subsequent substitution with an
alkyl halide.[9–11] Recently, we have described the prepara-
tion of well-defined NHC-Os complexes[10] and bis(NHC)-
Pd complex[11] 1 by direct metalation from the correspond-
ing imidazolium salts. Indeed, imidazolium chloride 2 re-
acts with Pd(OAc)2 without any additional base under re-
flux in THF to produce stable bis(NHC)-PdII complex 1
Scheme 1. Formation of complex 1 from salt 2 by direct metalation.
After the pioneering studies of Matsuda and co-workers
who used arenediazonium salts[13] as arylating agents, these
compounds have become an interesting substitute for aryl
halides in the palladium coupling reaction with olefins. An
interesting aspect of the Heck–Matsuda coupling is that the
reactions can be performed under “ligandless” conditions.
In that case, arenediazonium salts undergo oxidative ad-
dition with palladium with relative ease, but the subsequent
cationic intermediate is only stabilized by weakly coordinat-
ing solvents (or acetate if sodium acetate is used as base)
and can aggregate to form inactive Pd black; thus, a suitable
ligand can help in the turnover of the catalytic cycle.[14]
Four different ligands have been successfully employed in
this type of reaction with palladium loadings from 1 to
5 mol-%.[15] Among them, two catalytic systems based on
[a] Departamento de Química Orgánica, Facultad de Ciencias and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax: +34-965903549
E-mail: ipastor@ua.es
yus@ua.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200181.
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FULL PAPER
carbene ligands have been described. Andrus and co- procedure. Thus, three catalytic systems were chosen:
workers have described the catalytic system formed from Pd(OAc)2 (2 mol-%) without any ligand, Pd(OAc)2 (2 mol-
palladium acetate (2 mol-%) and 1,3-bis(2,6-diisoprop- %) with NHC precursor 2 (4 mol-%), and Pd(OAc)2 (2 mol-
ylphenyl)dihydroimidazolium chloride (2 mol-%), which ef- %) with NHC precursor 2 (10 mol-%). (2) Temperature:
ficiently produced the Heck coupled products (with 80– Two levels, that is, 36 and 60 °C, were selected to ensure
90% isolated yields) between alkenes (i.e., styrenes, acryl- that the reaction took place and that the temperature re-
ates, and acrylonitrile) and aryl diazonium tetrafluorobor- mained low enough because of the thermal stability of the
ates.[16] Additionally, the catalyst loading could be lowered diazonium salt. (3) Solvent: Four different solvents were
to 0.1% without any significant loss in yield for phenyl- and chosen, that is, acetonitrile, ethanol, and THF, which are
4-methoxyphenyl diazonium salts. Beller and co-workers frequently used in this coupling transformation, and also
described the preparation of well-defined monocarbenepal- water. (4) Equivalents of base: Sodium acetate is the base of
ladium(0) complexes with a 1,3-dimesitylimidazol-2-ylidene choice for the conventional Heck–Matsuda protocol,[14,15]
ligand. This type of complex (1 mol-% Pd) has catalyzed although other bases (e.g., CaCO3) can be employed. The
the coupling reaction between olefins (i.e., ethyl acrylate, 2- use of a base can be avoided while still obtaining good re-
ethylhexyl acrylate, and styrene) and different diazonium sults. Thus, three levels were considered for this factor: the
salts to yield the corresponding stilbenes and cinnamic es- no-base protocol and the use of 1 or 3 equiv. of base (i.e.,
ters in good yield (87–96%).[17] In our ongoing research re- NaOAc) with respect to the diazonium salt. (5) Substrate:
lated to functionalized NHC ligands for transition metals, Typical alkenes such as alkyl acrylates and styrene were se-
we have described[11] the use of complex 1 as an active pre- lected for setting the best conditions. Ethyl and tert-butyl
catalyst for the Hiyama coupling of aryl halides with trialk- acrylates, which in some cases have shown different reactiv-
oxy(aryl)silanes under a fluoride-free protocol[18] with low ity due to steric interactions, were employed.
levels of palladium (0.1 mol-%). Additionally, the active cat-
First set of selected reactions (18) were run over the
alyst could be also prepared in situ from palladium acetate course of 3 h under the corresponding conditions
and corresponding salt 2.[11] Herein, we wish to report the (Scheme 2).[20] After quenching with a saturated solution of
use of this catalytic system in the Heck–Matsuda reaction, NaHCO3, the reaction mixtures were analyzed by GLC by
under a very simple protocol, between different arenedi- using tridecane as an internal standard to provide a set of
azonium salts and different alkenes. We considered a statis- yield data. The results were analyzed, and a trend was ob-
tical study of the reaction conditions by employing a design tained for all the parameters (Figure 1). After this set of
of experiments (DoE) method.
reactions, we realized that the reaction is better performed
at lower temperature (36 °C) and in the absence of a base.
Additionally, the use of salt 2 as ligand proved to be supe-
rior compare with the ligandless reaction. Moreover, the 1:2
ratio for Pd/salt 2 was better than the 1:5 ratio. Regarding
the solvent, THF was found to be the best option. Al-
Results and Discussion
First of all, we considered different variables that could
have an impact on the yield. Therefore, we decided to opti-
mize the process by using a DoE approach.[19] Thus, the
coupling reaction between an alkene and a diazonium salt
was processed under a statistical study, for much better op-
timization, with the aim of maximizing the yield of the cou-
pling product.[18] The set of parameters (i.e., temperature,
solvent, equivalents of base, catalyst, and substrate; Table 1)
were compiled from the literature[14,15] and from our own
experience. The following considerations were taken into
account. (1) Catalyst: The use of arenediazonium salts com-
pared to aryl halides usually needs a high loading of palla-
dium (2–20 mol-%). Ligands can help to stabilize the active
palladium species, which reduces the amount of palladium
employed. We wanted to test and compare our hydroxy
functionalized NHC-Pd catalytic system with the ligandless Scheme 2. General DoE Heck–Matsuda Reaction.
Table 1. Parameters for the DoE and levels.
Parameter
Level 1
Level 2
Level 3
Level 4
Catalyst (mol-%)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
salt 2 (4)
Pd(OAc)2 (2)
salt 2 (10)
–
EtOH
NaOAc (3)
CH2=CH–Ph
–
–
T [°C]
Solvent
Base (equiv.)
Substrate
36
H2O
none
60
–
THF
–
CH3CN
NaOAc (1)
CH2=CH–CO2Et
CH2=CH–CO2tBu
–
2
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Heck–Matsuda Reactions Catalyzed by Hydroxyalkyl-NHC/Pd(OAc)2
Figure 1. Trends of the different parameters considered in DoE.
though CH3CN also gave a good yield of the coupling the use of a carbene ligand was not efficient in this solvent
product, a variety of byproducts were present in the reac- (Table 2, Entries 1, 5, and 6 vs. Entries 7–9). With the use of
tion mixtures.[20]
preformed complex 1, a lower yield was obtained (Table 2,
At this point, we tried the best set of reaction conditions Entries 1 & 15), which is in sharp contrast with our study
that were obtained from the DoE study. Thus, benzenediaz- on the Hiyama reaction[11] where similar results were ob-
onium tetrafluoroborate (3) was treated with ethyl acrylate tained with both catalytic systems.
(4) in THF in the presence of Pd(OAc)2 (2 mol-%) and salt
Taking a more critical look at the set of DoE data, we
2 (4 mol-%) in the absence of base at 36 °C for 3 h. The observed that the use of a base in ethanol had a detrimental
corresponding coupling product 5 was obtained in 99% effect on the yield of the final product.[20] In fact, in the
yield (Table 2, Entry 1). Under these reaction conditions, absence of a base in ethanol and THF, similar levels of ac-
the catalyst loading could be reduced to 0.5 mol-% of palla- tivity were achieved (Figure 2).[21] As a result, similar yields
dium without affecting its activity, but lower yields were were obtained when performing the reaction in ethanol in-
obtained with a loading of 0.1 mol-% of palladium (Table 2, stead of THF under the standard conditions (Table 2, En-
compare Entries 1–4). The reaction can also be performed try 10). In the absence of imidazolium salt 2 or by em-
in water, but with a lower yield (Table 2, Entries 7 & 8), and ploying preformed complex 1, a lower yield was obtained
in ethanol (Table 2, compare Entries 10, 14 and 17). Ad-
ditionally, the catalyst loading in ethanol could be also re-
duced to the same level without losing the activity (Table 2,
compare Entries 1–4 with 10–13). As a consequence, further
studies were performed with the use of the more benign
solvent ethanol.
Table 2. Catalyst loading for the Heck–Matsuda reaction.[a]
Entry
Solvent
x
y
Yield [%][b]
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
H2O
2
1
0.5
0.1
2
2
2
2
2
2
1
4
2
1
0.2
10
0
4
10
0
4
2
99
98
99
84
28
59
74
31
83
99
96
98
85
86
63
72
77
H2O
H2O
9
10
11
12
13
14
15
16
17
EtOH
EtOH
EtOH
EtOH
EtOH
THF
H2O
0.5
0.1
2
1
0.2
0
complex 1 (2 mol-%)
complex 1 (2 mol-%)
complex 1 (2 mol-%)
Figure 2. Trends refer to the amounts of base in ethanol (♦) and
THF (᭿).
EtOH
[a] Reaction performed with benzenediazonium tetrafluoroborate
(1 mmol) and ethyl acrylate (2 mmol) in the presence of the cata-
lytic system (see column) at 36 °C for 3 h. [b] Yield was calculated
by GLC analysis by employing tridecane as an internal standard.
The optimal conditions were employed for the Heck–
Matsuda reaction of a range of arenediazonium salts 3 with
ethyl and tert-butyl acrylates (4 and 6, respectively). Thus,
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I. Peñafiel, I. M. Pastor, M. Yus
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different diazonium salts, the acrylate, Pd(OAc)2, and NHC oxybenzene-, 3-chlorobenzene-, and 4-cyano-2-ethyl-
precursor 2 were mixed in ethanol[22] and stirred at 36 °C benzenediazonium tetrafluoroborates produced the ex-
for 3 h to produce expected cinnamate derivatives 5 and 7 pected coupling products in lower isolated yields (Table 3,
(Table 3). In all cases, the final products were isolated in Entries 16, 17, and 19). Interestingly, the coupling reaction
more than 90% yield when diazonium salts with either elec- between acrylamide and the diazonium salt bearing a 2-
tron-withdrawing or electron-donating groups were used methylphenyl group resulted in the preparation of cinn-
(Table 3, Entries 1–7 and 10–13). The use of a congested amide derivative 11d in 78% isolated yield (Table 3, En-
diazonium salt (i.e., 2-methylphenyldiazonium tetrafluoro- try 18).[24] Compound 11d, described as U-77863, has been
borate) gave also the coupling product in good isolated isolated from Streptomyces griseoluteus and has been re-
yield (Table 3, Entries 5 and 13). Coupling products 5h and ported to show significant anti-invasive and antimetastatic
5i arising from the reaction of ethyl acrylate and disubsti- effects.[25]
tuted benzenediazonium salts were obtained in lower yields
Finally, we tested the reaction with unactivated alkenes
(Table 3, Entries 8 & 9). The use of halogen (i.e., 4-iodo, such as cyclohexene 12. The reaction performed under the
4-bromo, and 3-chloro)-substituted benzenediazonium salts optimal conditions permitted the preparation of the corre-
gave exclusively the Heck–Matsuda coupling product sponding arylcyclohexene derivatives 13 in good yield and
(Table 3, Entries 4, 6 and 7), and no product from Mizo- as a single isomer (Scheme 3). Encouraged by these results,
roki–Heck coupling was detected. The coupling reaction cyclooctene and 1-octene were also coupled with benzenedi-
between styrene (8) and benzenediazonium salt produced azonium tetrafluoroborate, but unfortunately, unavoidable
expected (E)-stilbene 9 in moderate yield (42%), which was isomeric mixtures that could not be separated or charac-
improved to 88% by increasing the loading of the catalyst terized were obtained. Furthermore, arylation of nor-
(up to 2 mol-% Pd; Table 1, Entry 14). Additionally, we bornene (14) was also achieved in the presence of a reduc-
tried the reaction with more challenging and interesting ac- ing agent (i.e., Ph3SiH) to produce saturated bicyclic prod-
rylamide (10).[23] For this substrate, a higher amount of cat- uct 15 (Scheme 4).[26]
alyst (1 mol-% of Pd) was employed to produce cinnamide
(11a) in 82% yield from diazonium salt 3a (Table 3, En-
try 15). The use of other diazonium salts such as 4-meth-
Table 3. Heck–Matsuda coupling of arenediazonium salts with
ethyl acrylate, tert-butyl acrylate, styrene, and acrylamide.[a]
Scheme 3. Heck–Matsuda coupling of cyclohexene catalyzed by
Pd(OAc)2 and salt 2.
Entry
Ar
Y (compound) Product Yield [%][b]
1
2
3
4
5
6
7
8
Ph
4-(NO2)C6H4
4-MeOC6H4
3-ClC6H4
2-MeC6H4
4-IC6H4
4-BrC6H4
4-(CN)-2-EtC6H3
3,5-(CF3)2C6H3
Ph
4-(NO2)C6H4
3-ClC6H4
2-MeC6H4
Ph
CO2Et (4)
CO2Et (4)
CO2Et (4)
CO2Et (4)
CO2Et (4)
CO2Et (4)
CO2Et (4)
CO2Et (4)
CO2Et (4)
CO2tBu (6)
CO2tBu (6)
CO2tBu (6)
CO2tBu (6)
Ph (8)
5a
5b
5c
5d
5e
98
99
92
98
93
94
91
81
64
96
96
92
90
Scheme 4. Heck–Matsuda reaction of norbornene catalyzed by
Pd(OAc)2 and salt 2 in the presence of a reducing agent.
5f
5g
5h
5i
7a
7b
7c
7d
9
11a
11b
11c
11d
11e
Conclusions
9
10
11
12
13
14
15[d]
16[d]
17[d]
18[d]
19[d]
In conclusion, using DoE techniques, we have been able
to find a set of reaction conditions to productively perform
the Heck–Matsuda by employing a functionalized NHC as
a ligand for palladium. Thus, the catalytic system formed
in situ from Pd(OAc)2 and imidazolium salt 2 (in a 1:2 ra-
tio) allows the Heck–Matsuda reaction of different olefins
and arenediazonium tetrafluoroborates to be performed. In
comparison to other ligands that have been previously re-
ported, lower loadings of palladium have been achieved for
the Heck–Matsuda reaction with acrylates with the use of
this methodology. Additionally, with the use of the devel-
oped catalytic system, acrylamide was found to be a suitable
substrate for the Heck–Matsuda reaction under the reaction
conditions studied. The preparation of bioactive compound
U-77863 was achieved successfully through this protocol.
42 (88)[c]
82
Ph
CONH2 (10)
CONH2 (10)
CONH2 (10)
CONH2 (10)
4-MeOC6H4
3-ClC6H4
2-MeC6H4
12
20
78
36
4-(CN)-2-EtC6H3 CONH2 (10)
[a] Reaction performed with arenediazonium tetrafluoroborate
(1 mmol) and acrylate (2 mmol) in the presence of Pd(OAc)2
(0.5 mol-%) and salt 2 (1 mol-%) in EtOH (2 mL) at 36 °C for 3 h.
[b] Isolated yield of pure product after purification by chromatog-
raphy (silica gel, hexane/ethyl acetate mixtures). [c] The yield for
the reaction performed with Pd(OAc)2 (2 mol-%) and salt 2 (4 mol-
%) is given in parentheses. [d] Reaction performed with Pd(OAc)2
(1 mol-%) and salt 2 (2 mol-%).
4
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Heck–Matsuda Reactions Catalyzed by Hydroxyalkyl-NHC/Pd(OAc)2
2010, 122, 7094–7107; Angew. Chem. Int. Ed. 2010, 49, 6940–
6952.
Moreover, cyclohexene was effectively coupled without any
isomerization of the double bond to produce only the ex-
pected 1-arylcyclohexene.
[3]
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Organomet. Chem. 1997, 547, 357–366; b) D. S. McGuinness,
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[4]
Experimental Section
General Remarks: All commercially available reagents (Acros, Ald-
rich, Fluka) were used without further purification. Melting points
were determined with a Reichert Thermovar hot plate apparatus.
NMR spectra were recorded with a Bruker Avance 300 and a
Bruker Avance 400 (300 and 400 MHz for 1H NMR and 75 and
100 MHz for 13C NMR, respectively) by using, unless otherwise
stated, CDCl3 as the solvent and TMS as an internal standard.
Mass spectra (EI) were obtained at 70 eV with an Agilent 5973
spectrometer. HRMS analyses were carried out with a Finnigan
MAT95S Spectrometer. Infrared spectra were recorded with FTIR
Nicolet Impact 400D and Jasco 4100LE (Pike MIRacle ATR) spec-
trophotometers. Analytical TLC was performed on Merck alumi-
num sheets with silica gel 60 F254. Silica gel 60 (0.04–0.06 mm)
was employed for flash chromatography.
[5]
[6]
General Procedure for the Heck–Matsuda Coupling of Arenediazon-
ium Tetrafluoroborates with Alkenes: To a 10-mL vessel was added
Pd(OAc)2 (0.01 mmol, 2.2 mg), imidazolium salt 2 (0.02 mmol,
6.3 mg), and the corresponding arenediazonium salt 3 (1 mmol).
After 5 min, the corresponding alkene (2 mmol) was added drop-
wise. The vessel was sealed with a septum, and the mixture was
stirred at 36 °C for 3 h. The reaction mixture was filtered through
a pad of Celite and then extracted with CH2Cl2 (3ϫ5 mL). The
combined organic layer was filtered again through a pad of Celite
and anhydrous Na2SO4 and then concentrated in vacuo. Pure prod-
ucts 5, 7, 9, and 11 were purified by recrystallization (hexane) or
by chromatography (preparative TLC plates, hexane/ethyl acetate).
Yields are given in Table 3.
[7]
[8]
For some examples of phosphane-functionalized imidazolium
salts, see: a) C. Yang, H. M. Lee, S. P. Nolan, Org. Lett. 2001,
3, 1511–1514; b) H. M. Lee, P. L. Chiu, J. Y. Zeng, Inorg. Chim.
Acta 2004, 357, 4313–4321; c) K. L. Luska, A. Moores, Adv.
Synth. Catal. 2011, 353, 3167–3177.
For an example of a thioester-functionalized imidazolium salt,
see: D. Yuan, H. V. Huynh, Dalton Trans. 2011, 40, 11698–
11703.
R. Torregrosa, I. M. Pastor, M. Yus, Tetrahedron 2007, 63,
469–473.
B. Eguillor, M. A. Esteruelas, J. García-Raboso, M. Oliván, E.
Oñate, I. M. Pastor, I. Peñafiel, M. Yus, Organometallics 2011,
30, 1658–1667.
Supporting Information (see footnote on the first page of this arti-
cle): Physical, spectroscopic, and analytical data, as well as litera-
ture references for known compounds.
Acknowledgments
[9]
Financial support from the Ministerio de Ciencia e Innovación
(MICINN) of Spain (Project Nos. CTQ2007-65218, CTQ2011-
24165, Consolider Ingenio 2010 CSD2007-00006), the Generalitat
Valenciana (PROMETEO/2009/0349 and FEDER) is acknowl-
edged. I.P. thanks the MICINN for a predoctoral fellowship.
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I. Peñafiel, I. M. Pastor, M. Yus
FULL PAPER
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[20] The reaction in EtOH in the presence of other bases also gave
a lower yield of compound 7a: 53% (using 1 equiv. K2CO3),
73% (using 1 equiv. CaCO3), and 75% (using 1 equiv. of 2,6-di-
tert-butyl-4-methylpyridine). For further information regarding
the DoE reactions, see the Supporting Information.
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Received: February 15, 2012
Published Online: ᭿
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Heck–Matsuda Reactions Catalyzed by Hydroxyalkyl-NHC/Pd(OAc)2
Functionalized NHC Ligands
I. Peñafiel, I. M. Pastor,*
M. Yus* ............................................ 1–7
Heck–Matsuda Reactions Catalyzed by a
Hydroxyalkyl-Functionalized NHC and
Palladium Acetate
A hydroxy-functionalized NHC in combi-
nation with a palladium source allows the
Heck–Matsuda reaction to be carried out
between different arenediazonium salts and
various alkenes (i.e., acrylates, acrylamide,
styrene, and cyclohexene) The optimal con-
ditions to perform the reaction were deter-
mined by a design of experiments study.
Keywords: Carbene ligands / Palladium /
Alkenes / Nitrogen heterocycles
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