Synthesis and Catalytic Applications of [N,N]-Pyrrole Ligands for the Regioselective Synthesis of Styrene Derivatives

Article abstract of DOI:10.1002/adsc.201900365

We report the synthesis of two [N,N]-donor ligands (5 a–b) containing a 2-chalcogenazoline as the structural motif. These compounds were synthesized from a common intermediate Fischer type aminocarbene complex (3). The palladium-complexes of these [N,N]-donor ligands were successfully used as catalytic precursors in the Mizoroki-Heck coupling reaction between aryl halides and methyl acrylate, styrene and ethylene. For methyl acrylates, high yields with TOF values between 0.6 and 5.5×10⁵ h^?1 were obtained. In the case of ethylene, we reached high regioselectivities to obtain a diversity of styrene derivatives under soft pressure conditions, with good values of TON and TOF. (Figure presented.).

Full text of DOI:10.1002/adsc.201900365

Title: Synthesis and Catalytic Applications of [N,N]-Pyrrole Ligands for
the Regioselective Synthesis of Styrene Derivatives
Authors: Frank Hochberger, Salvador Cortés-Mendoza, David
Gallardo-Rosas, Alfredo R. Toscano, M. Carmen Ortega-
Alfaro, and Jose G López-Cortés
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900365
Link to VoR: http://dx.doi.org/10.1002/adsc.201900365

10.1002/adsc.201900365
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis and Catalytic Applications of [N,N]-Pyrrole Ligands
for the Regioselective Synthesis of Styrene Derivatives
Frank Hochberger-Roa,a Salvador Cortés-Mendoza,a David Gallardo-Rosas,b Ruben A.
Toscano,a M. Carmen Ortega-Alfarob and José G. López-Cortésa*
a
Universidad Nacional Autónoma de México, Instituto de Química, Circuito Exterior, Ciudad Universitaria, Coyoacán,
C.P. 04510, CdMx, Mexico. Phone: (+52)-555-622-4513; Fax: (+52)-555-616-2203; jglcvdw@unam.mx
Universidad Nacional Autónoma de México, Instituto de Ciencias Nucleares, Circuito Exterior, Ciudad Universitaria,
b
Coyoacán, C.P. 04510 CdMx, Mexico.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. We report the synthesis of two [N,N]-donor For methyl acrylates, high yields with TOF values between
ligands (5a-b) containing a 2-chalcogenazoline as the 0.6 and 5.5 x 105 h-1 were obtained. In the case of ethylene,
structural motif. These compounds were synthesized from a we reached high regioselectivities to obtain a diversity of
common intermediate Fischer type aminocarbene complex styrene derivatives under soft pressure conditions, with
(3). The palladium-complexes of these [N,N]-donor ligands good values of TON and TOF.
were successfully used as catalytic precursors in the
Mizoroki-Heck coupling reaction between aryl halides and
methyl acrylate, styrene and ethylene.
Keywords: [N,N]-Donor Ligands; C-C Coupling;
Nitrogen-Based Heterocycles; Oxazoline Ligands; Styrene
On the other hand, in addition to the variety of
frameworks used to obtain bidentate ligands, only a
few examples contain pyrrole as the main structural
motif,[5] which has proven quite efficient compared
with its aryl analogues.[6] The catalytic performance
of this kind of ligands has meant that entire families
Introduction
The palladium-catalyzed olefination of aryl halides
provides a very convenient method for forming
carbon-carbon bonds at unsubstituted vinylic
positions. The coupling partners generally involved in
this reaction include aryl halides and activated olefins
(e.g. acrylates). Particularly, when ethylene is used as
an olefin, this reaction has difficulties associated with
preventing overreaction and production of lateral
products, which results in poor selectivity of the
desired product. These challenges have been
overcome to some extent using some bulky ligands
(Figure 1),[1] in combination with palladium acetate
as a palladium source. Some preformed palladacycles
derived from CataCXium C® family have been also
used successfully. Despite these efforts, the reaction
conditions necessary to obtain the vinylated product
generally involve high temperature and ethylene
pressure, and inert conditions when arylphosphines
are used as a component of the catalyst.
Among the different ligands used for catalysis,
those containing an oxazoline ring in their structure,
specially 2-oxazolines are of outstanding importance,
due to their demonstrated activity and efficiency in
several catalytic applications.[2] Compared with the 2-
oxazolines, the 2-thiazolines have been less studied,[3]
nevertheless some reports describe that both ligands
show remarkable differences in their catalytic
performance.[4]
H
P(t-Bu)2
P
N
N
L1
L2
L3
R'
PPh2
PPh2
O
P
R
R
P
L7
L6
L4 R = OMe R' = H
L5 R = i-Pr R' = i-Pr
R'
OH
Pd
R
R
R
Cl
Pd
Cl
O
O
Pd
P
Pd
R
P
O
R
O
HO
R
R'
[Pd-2] R= Me
[Pd-3] R= p-ClC6H4 R'=Cl
[Pd-1] R= o-Tolyl
cataCXium C
R'=H
Figure 1. Representative ligands used in palladium-
catalyzed vinylation.
1
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10.1002/adsc.201900365
Advanced Synthesis & Catalysis
OH
of monodentate ligands based on 2-phosphanyl-1-
arylpyrrole ligands (PAP ligands) are marketed under
the name of CataCXium-P®. Their structural
arrangements involve aryl substituents connected to
the pyrrole nitrogen atom forming an N–C bond.
However, if the carbon group is replaced by an amine
functionality to generate an N–N bond, this amine-
based group can be an additional donor, which can be
coordinated with the metal center.[7]
H
N
(a)
(b)
OEt
(c)
N
N
N
N
N
Cr(CO)4
3 (97%)
N
Cr(CO)4
1
2 (92%)
(e)
(d)
In this context, we herein report an efficient
synthesis of two [N,N]-ligands based on pyrrole,
containing both an amino group and thiazoline or
oxazoline motifs as sources of the nitrogen donor
atoms. This structural arrangement favors the use of
these ligands and their palladium complexes under air
and moisture conditions, avoiding cumbersome
manipulations. Likewise, we have explored the
catalytic applications of these palladium complexes
in a Mizoroki-Heck coupling reaction using methyl
acrylate, styrene and ethylene. This last for obtaining
an extensive family of styrene derivatives in a
regioselective manner and under soft pressure
conditions.
S
O
S
(f)
N
N
N
N
N
N
HN
N
N
OH
5b (85%)
5a (91%)
4a (89%)
Scheme 2. Synthesis of [N,N]-ligands 5a-b. Reaction
conditions: (a) t-BuLi, THF, -78 ºC, N2, Cr(CO)6 (b)
Et3BF4, 0 ºC (c) Ethanolamine, NaH, Et2O, RT, N2 (d)
S8/NaBH4, EtOH, RT, N2, then 70 ºC, 12 h (e) I2/Py, Et2O,
RT, 30 min (f) MsCl, Et3N, CH2Cl2, 0 ºC, 15 min.
Results and Discussion
As shown in the retrosynthetic analysis (Scheme 1),
the proposed [N,N]-ligands 5 could be obtained by an
intramolecular annulation of the corresponding
chalcogenamide 4, these last accessible through a
demetallation reaction of the Fischer type
aminocarbene complex 3. This complex can be easily
obtained from the Fischer type ethoxycarbene
complex 2.
Figure 2. ORTEP representation of 2, ellipsoids are shown
at 30% probability level.
Intramolecular
Demetallation
annulation
Cr(CO)5
E
E
N
N
N
N
N
N
HN
HN
N
chelating ring. The geometry around metal center is
octahedral distorted, two carbonyl molecules are
situated in the apical positions with and bond angle of
C(13)-Cr(1)-C(14) 169.6°(2). Bond distances and
angles are in accordance with the literature values for
classical Fischer carbene complexes.[9]
Complex 3 was successfully obtained by the
aminolysis reaction of 2 as a stable solid compound
with a 97% yield. After that, we proceeded to the
synthesis of thioamide 4a using a demetallation
reaction. This compound was obtained with an 89%
yield, and its structure was confirmed by single
monocrystal for X-ray diffraction analysis (SI). The
next step involved an intramolecular cyclization,
following a standard procedure,[10] affording 5a in
excellent yield (Scheme 2). Likewise, the structural
arrangement for 5a was unequivocally established by
X-ray diffraction analyses (Figure 3). We crystalized
this compound as a protonated species (5a’), which
was obtained after the reaction of 5a with HPF6. We
confirmed the formation of a thiazoline ring, which
4
OH
OH
Aminolysis
3
5
Carbene
synthesis
Cr(CO)5
OEt
N
N
1
N
N
2
Scheme 1. Retrosynthetic approach for obtaining ligands 5.
Based on this plan, we synthesized the ethoxycarbene
Fischer complex 2 following a modified method
previously reported by our group,[8] obtaining 2 as a
dark red solid in 92% yield (Scheme 2). The
structural arrangement of 2 was fully confirmed by
X-ray diffraction analysis (Figure 2), which revealed
that the carbenic carbon atom is directly bonded at
the α position of the pyrrole moiety. The dimethyl
amino group and the carbenic carbon form a five-
2
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10.1002/adsc.201900365
Advanced Synthesis & Catalysis
Once obtained the ligands 5a-b, we studied their
coordination ability to Pd(II), by treating 5a-b with
PdCl2(CH3CN)2 in CHCl3, obtaining in both cases, an
orange powder almost insoluble in organic solvents,
but very stable under moisture conditions. The
limited solubility of these complexes does not make it
possible to carry out a complete spectroscopic
characterization and although the elemental analyses
match well with the formation of a PdCl2(2-N,N’-
Ligand) complex, we decided to perform the catalytic
tests using these palladium species formed in situ.
In a first attempt, we decided to explore the
catalytic performance of these ligands using as a
model reaction the cross-coupling between methyl
acrylate and 4-iodotoluene. To determine optimal
conditions, the reaction was performed under
microwave heating in aerobic conditions, evaluating
parameters such as the base, the solvent, the reaction
time and the catalyst loading.
The initial exploration of reaction conditions was
focused on catalyst loading using the ligand 5a and
PdCl2(CH3CN)2, as a palladium source and DMF as
solvent. In these conditions, a 4 bar of pressure was
reached into the microwave equipment. We found
that 0.05% mol of 5a/[Pd] provides the best result,
with optimum yields of the coupled product (Table 1,
entry 3). But, when we decreased the catalytic load to
0.01% mol, we obtained the best TON and TOF
(entry 4). The type of base was also screened (e.g.
NaOAc, K2CO3, K3PO4), and we found that the other
bases gave low yields (Table 1, entries 5-8).
Figure 3. ORTEP representation of 5a’, ellipsoids are
shown at 30% probability level.
adopts an envelope conformation, with C(7) as a flap.
The distances C(6)-N(3), 1.298 (5)Å and C(6)-S(1),
1.718(4)Å are similar to those found in other
thiazoline analogues.[11] Compound 5a’ exhibits a
…
hydrogen-bond interaction between N(2) H(3A)-
N(3), 2.104Å, forming a six-member ring, which
reveals the predisposition of this ligand to coordinate
a metal in a 2-N,N’-chelating mode.
On the other hand, we found that the complex 3
can be efficiently transformed into 5b, when it is
exposed to the oxidative action of iodine in the
presence of pyridine as additive. This reaction is
sensitive to the amount of these reagents and is only
effective when a stoichiometry 5:3 I2/pyridine is used.
Table 1. Standardization of conditions for the C-C coupling reaction.a
O
5a / [Pd]
I
O
Solvent
Base, MW
O
O
Me
Me
6a
7a
Entry
Base
Solvent
Time
(min)b
2
2
1
1.5
3
7
4
4
12
10
12
8
7
15
15
% mol
5a/[Pd]
0.5
Yield
(%)c
69
88
92
81
70
57
72
68
43
0
TON
TOF
(h-1)
1
2
3
4
5
6
7
8
NEt3
NEt3
NEt3
NEt3
NaOAc
Na2CO3
K2CO3
Na3PO4
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Ethylene glycol
EtOH
CH3CN
DMF
138
880
4140
26400
110400
324000
28000
9771
21600
20400
4300
-
0.1
0.05
0.01
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.01
0.01
1840
8100
1400
1140
1440
1360
860
9d
10e
11e
12f
13g
14h
-
-
7
-
84
73
85
79
1680
1460
8500
7900
12600
12514
34000
31600
DMF
DMF
DMF
15h,i
a
Reaction conditions: 0.5 g (2.3 mmol) of 4-Iodotoluene, 0.22 mL (2.4 mmol) of methyl acrylate, 3.45 mmol of base, 5
b
mL of solvent and 5a/[Pd] as catalytic precursor at 160 °C. Time reaction based on total consumption of 4-Iodotoluene
determined by TLC. Isolated yield after SiO2 flash chromatography. Reaction conducted at 200 ºC. Reaction
conducted at 90 ºC. Reaction conducted with PdCl2(PPh3)2 as a catalytic precursor. Reaction conducted with Pd(OAc)2
+ 2 PPh3 as catalytic precursor. Reaction conducted in a sealed tube, under thermal heating conditions. Reaction
conducted in the presence of a Hg(0) drop.
c
d
e
f
g
h
i
3
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10.1002/adsc.201900365
Advanced Synthesis & Catalysis
Likewise, we tested other solvents such as ethylene
We thus decided to explore the catalytic performance
of ligands 5a-b, using less activated olefins such as
styrene and ethylene. Considering the physical
properties of ethylene, we adapted the reaction
conditions using a sealed tube and using styrene as
model substrate, to study its behavior before
extrapolating the catalytic application to ethylene. In
the first place, we observed important differences,
using the same reaction conditions, no conversion
was detected so, we modified the catalytic load to
0.05 % mol of 5b[PdCl2] (Table 3, entries 1-3), and it
was necessary to increase the reaction time to 4 h,
obtaining the corresponding stilbene with a 74% yield.
Subsequently, we increased the catalytic load to
0.1 % mol, comparing the catalytic performance at 1
and 2 h of reaction time (Table 3, entries 4-7).
Although both ligands gave excellent yields of the
corresponding stilbene, the catalytic performance of
ligand 5a was lower than 5b, giving us an initial idea
about the its catalytic activity using this kind of
substrates. In all cases, the reaction was
regioselective to the formation of the 4-
methylstilbene, and only traces of the corresponding
gem-isomer were detected.
glycol, ethanol and acetonitrile, but only with
ethylene glycol, the coupling product was obtained in
low yield, making it necessary to increase the
temperature to 200 ºC, to achieve the same pressure
conditions (Table 1, entries 9-11). Also, two control
experiments using commercial palladium complexes
were conducted, in both cases good yields of the
coupling product were obtained, with longer reaction
times (Table 1, entries 3 and 12-13).
The effectiveness of the microwave irradiation and
conventional heating for Heck reaction were also
compared. Thus, we performed the Heck reaction
under thermal conditions using a sealed tube. In this
case, we obtained a similar yield of the coupling
product to that obtained with the microwave method,
increasing the reaction time up to 15 minutes (entries
4 and 14). To discard the possible formation of Pd
nanoparticles, we conducted
a
mercury drop
experiment under thermal conditions and using a
sealed tube, obtaining a similar yield of 7a (Table 1,
entries 14 and 15). Considering this result, a similar
behavior would be expected under microwaves
heating.
With the best conditions for this coupling reaction
(Table 1, entry 4), we proceeded to study the scope of
the reaction, choosing a variety of aryl iodides (Table
2). The electronic nature of the substituents seems to
have no effects on the product yield. With the
exception of 6c containing an NH2 coordinating group
on the aryl ring (34%), all substrates were cleanly
converted to the corresponding methyl cinnamate
with isolated yields, after flash chromatography
ranging from 92-96%. The coupling reaction requires
in short reaction times, and with TOF values between
0.6 and 5.5 x 105 h-1.
Table 3. Scope of the C-C coupling reaction using styrene
as coupling partner. a
5 / [Pd]
I
DMF
NEt3, 160 ºC
Me
Me
% mol Time Yield
[Pd]
TOF
(h-1)
Entry
Ligand
TON
(h)b
(%)c
1
2
3
4
5
6
7
0.01
0.05
0.05
0.1
0.1
0.1
0.5
0.5
4
2
1
-
-
-
5a
5a
5a
5a
5a
5b
5b
27
74
94
78
>99
90
540
1480
940
780
970
900
1080
370
470
780
485
900
Table 2. Scope of the C-C coupling reaction.a
O
5a / [Pd]
I
O
2
1
DMF
NEt3, MW
4 bar
O
0.1
O
R
a Reaction conditions: 0.5 g (2.3 mmol) of 4-iodotoluene,
0.27 mL (2.4 mmol) of styrene, 0.5 mL (3.45 mmol) of
NEt3, 5 mL of DMF and 5/[Pd] as catalytic precursor at
R
6a-i
7a-i
Time Yield
(min)b (%)c
TOF x
Entry
p-R
TON
105 (h-1)
b
160 °C. Time reaction based on total consumption of 4-
iodotoluene determined by TLC. c Isolated yield after SiO2
flash chromatography.
1
2
3
4
5
6
7
8
9
CH3
OCH3
NH2
H
Br
COCH3
COOCH3
CF3
3
2
3.5
1
4
5
4
3.5
5
92
93
34
92
96
97
97
97
94
9200
9300
3400
9200
9600
9700
9700
9700
9400
1.84
2.79
0.58
5.52
1.44
1.16
1.45
1.66
1.13
To test the catalytic performance of ligands 5a-b,
using a more challenging olefin, we extrapolate again
the result obtained in microwaves conditions to a
sealed tube using the catalytic system 5a[Pd], and
ethylene pressure equal to that used in the microwave
tube, using DMF as a solvent. In the first experiment
(Table 4, entry 1), we obtained a good conversion of
6a, the compound of interest 8a, and the products of
over-coupling 9a and 10a. To avoid the formation of
9a and 10a, we decreased the catalytic load of 5a,
and increased the reaction time (Table 4, entries 2-3).
Nevertheless, no significant changes were observed
in the 9a/10a ratio. When we conducted this reaction
NO2
a Reaction conditions: 2.0 mmol of aryl iodide, 2.2 mmol
of acrylate, 3 mmol of NEt3, 5 mL of DMF and 0.01%mol
b
of 5a/[Pd] at 160 °C, 4 bar of pressure. Time reaction
based on total consumption of aryl iodide determined by
TLC. c Isolated yield after SiO2 flash chromatography.
4
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10.1002/adsc.201900365
Advanced Synthesis & Catalysis
Table 4. Standardization of the conditions for the C-C coupling for the formation of 4-methyl styrene 8a. a
5 / [Pd]
Ethylene
I
Et3N,DMF
10a
8a
9a
6a
Ratio
TONd
TOF
(h-1)e
time
(h)
% mol
L/[Pd]
Conversion
Entry
Ligand
T (°C)
P (bar)
(%)b,c
8a/
9a/
10a
1
1
1
2
1
1
1
1
1
2
2
2
2
2
2
160
160
160
80
4
4
4
4
4
6
6
6
6
6
6
6
6
6
1
0.5
0.5
0.5
0.5
0.5
0.5
0.25
0.25
0.25
0.25
0.25
0.25
0.25
89
84
83
0
72
68
50
7
3
7
-
-
1
-
-
-
13
-
-
21
29
43
-
-
15
6
-
-
11
-
-
89
168
166
-
89
168
83
-
70
172
168
252
188
78
5a
5a
5a
5a
5a
5a
5b
5a
5b
--
2c
3
4
5
6
7
8
9
-
120
160
160
160
160
160
160
160
160
160
35
86
84
63
94
39
72
90
15
0
100
84
94
100
100
76
100
100
100
-
70
172
168
252
376
156
288
360
10
11f
12g
13h
144
180
5b
5b
5b
5b
-
-
-
-
14i
-
-
a
All reactions were carried out in a Parr reactor, using 0.5 g (2.3 mmol) of 6a, ethylene, 5 mL of DMF, 1.5 equivalents
b
c
triethylamine and different % mol of 5/[PdCl2(CH3CN)2]. Conversion calculated by NMR. Conversion determined by
GC/MS shows the same results obtained by H NMR. d Calculated from the conversion. TON / time (h). Reaction
conducted in a Parr reactor, using 1.0 g (4.6 mmol) of 6a, ethylene, 10 mL of DMF, 1.5 equivalents triethylamine and
0.25 % mol of 5a/[PdCl2(CH3CN)2]. g Reaction conducted in a Parr reactor, using 1.0 g (4.6 mmol) of 6a, ethylene, 5 mL
1
e
f
h
of DMF, 1.5 equivalents triethylamine and 0.25 % mol of 5a/[PdCl2(CH3CN)2]. Reaction conducted in the presence of a
Hg(0) drop. i Reaction conducted in the presence of a CS2 as a poisoning additive.
at lower temperature (80 °C), the starting material 6a
was completely recovered (Table 4, entry 4). So, we
decided to increase the ethylene pressure and
achieved a better proportion of the styrene/ sub-
products/ starting material. Under these conditions,
we tested 2-oxazoline 5b (Table 4, entries 6-7). The
catalytic activity of the system 5b/[Pd] is similar to
that obtained with ligand 5a and proceeds
regioselectively, producing the styrene 8a as the main
product.
regioselectivity. During the course of these reactions
we detected that the pressure drops over time,
indicating the consumption of ethylene.
In all experiments carried out for adjusting the best
reaction conditions using ethylene, the presence of a
residual black material was not detected.
Nevertheless, to discard the possible presence of
palladium nanoparticles, we carried out two
additional experiments using a mercury drop test and
CS2 as poisoning additives12 (Table 4, entries 13-14).
In the first case, we detected an important decrease in
the conversion but when CS2 was used as a poisoning
additive no conversion was obtained recovering the
starting aryl iodide. These results are applicable to the
possible participation of heterogenous species when a
worse coordinating olefin such as ethylene is used as
a partner coupling.
To explore the scope of this reaction, we used a
variety of aryl iodides, including electron-
withdrawing and electron-releasing groups (Table 5).
We obtained good to excellent conversions ranging
from 75-99%, and excellent regioselectivities for the
formation of styrene derivative 8, except for 4-
iodoaniline, which did not react under this reaction
condition (Table 5, entry 3). To avoid the possible
coordination of substrate 6c with the catalytic system,
we decided to functionalize this aryl iodide, and a
reaction with the amide 6m was conducted under the
To evaluate the real effectiveness of ligands 5a-b, we
decreased the catalytic load again (Table 4, entries 8-
9), finding that the catalytic system formed by the
ligand 5b is more efficient and active in promoting
this coupling reaction in a regioselective manner,
with a catalytic load of 0.25%, using 6 bar of
ethylene pressure (entry 9). In both cases, 8a is
obtained with the same regioselectivity and no over-
coupling products are observed. Likewise, a control
experiment
was
conducted
only
using
PdCl2(CH3CN)2 under the same reaction conditions
(Table 4, entry 10). The results reveal that both
[N,N]-donor ligands modify not only the catalytic
activity but the regioselectivity of this reaction.
We also carried out two experiments for screening
both the scalability and the concentration effect on
the catalytic activity. In both cases, a slightly lower
yield of 9a was obtained with the same
5
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10.1002/adsc.201900365
Advanced Synthesis & Catalysis
Table 5. Scope of the C-C coupling reaction using the 5b/[PdCl2(CH3CN)2] as catalytic system. a
5b / [Pd]
Ethylene
I
R
Et3N,DMF
R
R
R
R
R
10a-m
8a-m
9a-m
6a-m
Time Conversion
(h)
2
2
2
Yield
ratio
TOF
TONe
Entry Substrate
R
(%)b,c
94
90
94
-
(%)d
78
75
68
-
8
9
-
-
-
-
-
6
-
-
-
-
-
-
-
-
-
-
-
-
10
-
-
-
-
4
-
-
-
-
-
-
-
-
-
-
-
-
(h-1)
1
2
p-CH3
100
100
100
-
96
94
100
100
100
100
100
100
100
100
100
100
100
100
312
292
272
-
156
146
136
-
6a
6a
6b
6c
6d
6e
6f
p-CH3
p-OCH3
p-NH2
H
3c
4
2
5
6
7
2
2
2
2
2
1
2
2
2
2
2
2
84
87
95
96
88
>99
93
75
87
99
93
30
2
83
80
70
64
47
71
87
53
85
78
67
26
-
332
320
192
256
188
284
348
212
340
312
268
104
-
166
160
96
128
94
284
174
106
170
156
134
52
p-Br
p-COCH3
p-COOCH3
p-CF3
p-NO2
p-CN
m-CH3
o-CH3
p-NHAc
p-NO2
p-MeO
p-NO2
p-NO2
8
9
6g
6h
6i
6j
6k
6l
10
11
12
13
14
15
16
17
18
6m
6i f
6g
6i h
6i h
2
-
20
3
-
-
-
-
a All reactions were carried out in a Parr reactor, using 2.0 mmol of 6, 5 mL of DMF, 3.0 mmol triethylamine and 0.25 %
mol of 5b / [PdCl2(CH3CN)2], at 160 °C using 6 bar of ethylene. Conversion calculated by H NMR. c Conversion
b
1
determined by GC/MS shows the same results obtained by H NMR. d Isolated yield after SiO2 flash chromatography.
1
e
Calculated from the yield obtained. f 4-bromonitrobenzene was used as substrate. g 4-bromoanisole was used as substrate. h
4-chloronitrobenzene was used as substrate.
same reaction conditions, achieving complete
conversion to the corresponding N-(4-vinylphenyl)-
acetamide (Table 5, entry 13). Due to the relative
lower boiling point and the high vapor pressure of all
styrene derivatives, in general the yields obtained
after purification by flash chromatography are lower
than those calculated by NMR. This problem is
solved in part when the reaction is scaled to 1 g of the
starting aryl iodide.
Finally, to prove the effectiveness of the 5b/[Pd]
catalytic system, we decided to explore the reactivity
of other aryl halides. When the reaction was
conducted with 4-bromonitrobenzene, the styrene
product was obtained regioselectively with a 93 % of
conversion (Table 5, entry 15). But when we tested 4-
bromoanisole, the styrene derivative was obtained
with a 30 % conversion, making evident the catalytic
limitations of this system to bromoaryl derivatives
containing electron-releasing groups. When 4-
chloronitrobenzene was used, the reaction was very
slow, and even after 20 h of reaction, we only
obtained traces of the 4-nitrostyrene (Table 5, entries
17-18).
begins with the coordination of 5 to the palladium
precursor giving the corresponding palladium
complex 5-[PdCl2], this species can react with the
olefin (or NEt3) favoring the formation of a molecular
palladium (0) species (A), which behaves as the
catalytic species, giving rice to the catalytic cycle
generally accepted for the Heck coupling reaction.13
When we used a -acid olefin such as methyl acrylate,
the reaction occurred very rapidly and no Pd
nanoparticles were detected (Table 1, entry 15).
However, when ethylene was used, the formation of
nanoparticles (Table 4) made evident that the olefin
coordination step to give (D) must be less effective as
a result of the high electron density on the palladium
center, making it necessary to increase both the
catalytic load and the reaction time. This effect is
reduced when 5b is used as a ligand.
Likewise, the Pd(0) material can be formed from: a)
by direct de-coordination of (A) and b) after the
reductive elimination reaction in the intermediate (H).
In any case, the Pd(0) formed must re-enter to the
cycle, making it possible to explain the
regioselectivity observed in all styrene derivatives
obtained.
Based on the experimental evidences, a tentative
proposal for the Heck reaction using the complex
5[Pd] is described in Scheme 3. Thus, the first step
6
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10.1002/adsc.201900365
Advanced Synthesis & Catalysis
E
E
PdCl2(CH3CN)2
DMF
N
N
N
N
N
N
Pd
Cl
5a, E=S
5b, E=O
Cl
5-[PdCl2]
Et3N
R
D
DMF
R= H, Ph, C(O)OMe
H
E
R
N
E
N
Pd
DMF
(A)
N
R
N
N
N
Pd
DMF
Reductive
elimination Et3NH
+
(B)
Et3N
Oxidative
addition
Ar
X
5
-DMF
E
Pd(0)
N
E
E
-X-
N
N
N
N
N
N
Pd
N
N
X
H
+
Pd
Pd
(H)
X
DMF
R
Ar
Ar
(C)
(D)
Ar
b-H elimination
after C-C rotation
E
E
R
N
N
N
N
N
N
Pd
+
Pd
E
N
X
N
N
Ar
Ar
R
R
+
Pd
(G)
(E)
insertion
DMF
-
X
Ar
R
(F)
Scheme 3. Proposed catalytic cycle for the Heck coupling reaction using the complexes 5/[Pd].
Table 6. Catalytic performance of different palladium systems in the Heck coupling reaction for obtaining 4-methylstyrene
[Pd]
Ethylene
X
+
Base, DMF
10a
8a
6a
Entry Palladium
catalyst
X
Conditions
Ethylene Time Conversion
Ratio TON
8/10
TOF Ref
(h-1)
pressure
(bar)
(h)
1
2
3
4
Br
Ia
I
10.3
1
73
87
78
94
1:0
1:0
1:0
1:0
146
17.4
780
376
146
70
1c
1a
1h
CataCXium C
L2/Pd(OAc)2
L6/Pd(OAc)2
5b[Pd]
0.5 % mol [Pd],
Bu3N, 125 ºC, MW
5 %mol [Pd], TBAI,
120 ºC, Toluene
15
5.5
6
0.25
3
260
188
0.1% mol [Pd], H2O
I
2
This
work
0.25 % mol [Pd],
NEt3, 160 ºC
a) 3-Iodotoluene was used as a substrate.
Comparing the catalytic performance of 5b[Pd] in
this reaction with the results obtained for other
catalytic systems (Table 6), we observed that our
catalytic system displays a similar behavior to that of
other catalytic systems involving bulky ligands. This
catalytic system is robust, air-moisture stable and
operates under soft pressure conditions.
7
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10.1002/adsc.201900365
Advanced Synthesis & Catalysis
flash column chromatography on silica-gel to give the
corresponding methyl cinnamate.
Conclusion
In summary, we have found a new methodology to
General procedure for the synthesis of styrene
derivatives. A 10 mL vial was filled with 5 mL of DMF
and then the ligand 5 and Pd(CH3CN)2Cl2 which reacted
during 5 minutes, after that the corresponding aryl iodide
(2 mmol), and triethylamine (0.42 mL, 3.0 mmol) were
added. The vial was introduced into a stainless-steel
reactor, which was charged with ethylene at 6 bar of
pressure and placed in an oil bath at 160 ºC. Once the
reaction was completed, the reactor was cooled to room
temperature, the system was decompressed. The reaction
mixture was diluted with 20 mL of water and extracted
with hexane or ethyl acetate (3 × 10 mL). The combined
organic layers were dried over anhydrous sodium sulfate
and the solvent eliminated under vacuum. The conversion
easily obtain two novel [N,N]-donor ligands
containing 2-chalcogenazolines as structural motifs,
in high global yields and using as a common
intermediate an aminocarbene Fischer complex.
These [N,N]-donor ligands were coordinated to
palladium in situ and used as catalytic precursors in
the Heck coupling reaction between different aryl
halides and ethylene, under soft pressure conditions,
affording a variety of styrene derivatives in a
regioselective and quantitative conversion ranging of
75-99.9 %. The nature of the chalcogen included in
these [N,N]-donor ligands impacts directly on the
activity of their palladium complexes, and the
palladium complex containing the ligand 5b is more
active. These results indicate that the oxazoline motif
included in 5b, favors both the stability and the [2-
N,N´]-coordination to the palladium center, whereas
the incorporation of sulfur probably favors a high
electron density on the palladium center that modifies
its catalytic performance. Likewise, the experiments
conducted in the presence of poisoning additives
show that the nature of the olefin partner can modify
the course of the coupling reaction. In the first case,
methyl acrylates can contribute to the stabilization of
the palladium intermediates responsible for the
catalytic activity favoring a homogenous catalytic
system. In the case of ethylene, the possible
formation of nanoparticles was evident. The ligands
5a-b play an important role in the stabilization of the
catalytic palladium species. Further studies on the
scope of other catalytic applications with these
ligands, and the precise mechanism for this
palladium-catalyzed reaction are ongoing in our
laboratory.
1
was determined by H NMR and GC/MS methods. The
crude product was finally purified by flash column
chromatography on silica-gel to give the corresponding
styrene derivative.
Acknowledgements
The authors would like to acknowledge the technical assistance
provided by M. Paz Orta, Hector Rios Olivares, Luis Velasco and
Javier Pérez. We also thank to CONACYT for the 285722 project
and the Ph.D. grant extended to F. Hochberger-Roa and S.
Cortés-Mendoza.
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9
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10.1002/adsc.201900365
Advanced Synthesis & Catalysis
FULL PAPER
Control of electronic
density
Synthesis and Catalytic Applications of [N,N]-
Pyrrole Ligands for the Regioselective Synthesis of
Styrene Derivatives
Electron releasing
backbone
E
2-Chalcogenazoline
N
N
N
Hemilabile group
N-Chelating
5a, E =S
5b, E =O
Pd
Cl
Cl
R
Adv. Synth. Catal. Year, Volume, Page – Page
10 examples
yields
92-99%
R= COOMe, Ph R'
5a[Pd]
Frank Hochberger-Roa, Salvador Cortés-Mendoza,
David Gallardo-Rosas, Ruben A. Toscano, M.
Carmen Ortega-Alfaro and José G. López-Cortés*
H
H
H
I
+
R = H
R
5b[Pd]
6 bar
R'
14 examples
yields
77 - 87%
R'
R'= p-Me, m-Me, o-Me, p-OMe, H, p-Br, p-Ac,
p-COOMe, p-CF3, p-NO2, p-CN, p-NHAc
10
This article is protected by copyright. All rights reserved.