N-Heterocyclic carbene palladium (II)-pyridine (NHC-Pd (II)-Py) complex catalyzed heck reactions

Article abstract of DOI:10.1080/00397911.2021.1919711

A mild, efficient, and practical catalytic system for the synthesis of highly privileged stilbene pharmacophores is reported. This system uses N-heterocyclic carbene palladium (II) Pyridine (NHC-Pd (II)-Py) complex to catalyze the formation of carbon-carbon bonds between olefin derivatives and various bromide. This simple, gentle and user-friendly method can offer a variety of stilbene products in excellent yields under solvent-free condition. And its scale-up reaction has excellent yield and this system can be applied to industrial fields. The utility of this method is highlighted by its universality and modular synthesis of a series of bioactive molecules or important medical intermediates.

Full text of DOI:10.1080/00397911.2021.1919711

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
N-Heterocyclic carbene palladium (II)-pyridine
(NHC-Pd (II)-Py) complex catalyzed heck reactions
Dan Li, Qingqiang Tian, Xuetong Wang, Qiang Wang, Yin Wang, Siwei Liao,
Ping Xu, Xin Huang & Jianyong Yuan
To cite this article: Dan Li, Qingqiang Tian, Xuetong Wang, Qiang Wang, Yin Wang, Siwei Liao,
Ping Xu, Xin Huang & Jianyong Yuan (2021) N-Heterocyclic carbene palladium (II)-pyridine (NHC-
Pd (II)-Py) complex catalyzed heck reactions, Synthetic Communications, 51:13, 2041-2052, DOI:
10.1080/00397911.2021.1919711
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SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 13, 2041–2052
https://doi.org/10.1080/00397911.2021.1919711
N-Heterocyclic carbene palladium (II)-pyridine (NHC-Pd (II)-
Py) complex catalyzed heck reactions
Dan Li, Qingqiang Tian, Xuetong Wang, Qiang Wang, Yin Wang, Siwei Liao,
Ping Xu, Xin Huang, and Jianyong Yuan
Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing,
PR China
ABSTRACT
ARTICLE HISTORY
Received 10 January 2021
A mild, efficient, and practical catalytic system for the synthesis of
highly privileged stilbene pharmacophores is reported. This system
uses N-heterocyclic carbene palladium (II) Pyridine (NHC-Pd (II)-Py)
complex to catalyze the formation of carbon-carbon bonds between
olefin derivatives and various bromide. This simple, gentle and user-
friendly method can offer a variety of stilbene products in excellent
yields under solvent-free condition. And its scale-up reaction has
excellent yield and this system can be applied to industrial fields.
The utility of this method is highlighted by its universality and
modular synthesis of a series of bioactive molecules or important
medical intermediates.
KEYWARDS
NHC-Pd (II)-Py; aromatic
bromides; olefins;
stilbene; synthesis
GRAPHICAL ABSTRACT
R
iPr
iPr
1
iPr Cl
Pd N
Cl
N
N
Ar
Ar
R
Br
R
1
(0.01eq) NHC-Pd (II)-Py
(0.3eq) Cs CO ,100 °C,12 h
Ar
R
O
iPr
O
2
3
O
R
O
NHC-Pd (II)-Py
Free solvent,easy to synthesis of 22 examples,yield up to 99%
Introduction
The stilbene scaffold is a key pharmacophore in sunscreen,[1] natural products[2,3] and
pharmaceuticals[4,5] that accomplish a wide range of important functions (a small sam-
pling of which are provided in Scheme 1). Due to the importance of stilbene scaffold in
the synthesis of leading molecules,[6] a variety of preparative methodologies have been
developed. Particularly, the Heck reaction was used as one of the important methods
for the synthesis of stilbene and its analogues.[7]
The Heck reaction was discovered by Mizoroki[8] and Richard F Heck[9] in the early
1970s, which has been proven to be one of the most important methods for carbon-car-
bon formation between organic halides and olefins in organic chemistry. In the past
40 years, the Heck reaction has been widely used in many organic synthesis which
includes the synthesis of biologically active molecules,[6,10] natural products,[11] fine
CONTACT Jianyong Yuan
yuanjianyong@cqmu.edu.cn
Department of Medicinal Chemistry, College of Pharmacy,
Chongqing Medical University, Chongqing 400014, PR China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

2042
D. LI ET AL.
Scheme 1. Biologically active stilbene derivatives.
chemicals,[1] active pharmaceutical ingredients (APIs).[12] It now belongs to an essential
section of palladium-catalyzed cross-coupling reactions.[13]
The traditional Heck reaction usually couples aryl halide (C-halogen bond) with ole-
fin in the presence of a palladium catalyst.[14] Later, it was reported that different
ligands, metal sources, or metal sources substrates were used in the Heck reaction sys-
tem. In the past ten years, scientists have discovered many highly efficient homogeneous
palladium-containing catalystic systems. According to the difference of organic ligands
coordinated with metal palladium, the reaction can be divided into a variety of catalytic
systems, which contain electron-rich, sterically hindered phosphorus ligands,[15] nitro-
gen ligands[16,17] sulfur ligand[18] and N-heterocyclic carbene (NHC)[19] ligand. The
Heck reaction is a powerful catalytic method for carbonꢀcarbon (CꢀC) bond formation
in synthetic organic chemistry. Currently, various aryl substitution reagents that operate
under palladium catalysis instead of aryl halides have been developed, such as diazo-
nium salts,[20] aniline,[21] nitrobenzene,[22] phenylboronic acid[23] have been used for
the Heck reaction. The wide application of Heck reaction in organic synthesis urges
many scientists to find more effective, cheaper and readily available catalytic systems.
Subsequently, the catalytic system of iron,[24,25] nickel,[26] indium,[27] cobalt,[28] selen-
ium[29] metal complexes have been reported in the literature for Heck reaction
(Scheme 2).
Transition metal carbene complexes are one of the frontiers in the research of metal
organic chemistry. Since Fischer[30] introduced carbene into inorganic and metal-
organic chemistry in 1964, carbene derivatives have been widely used in organic reac-
tions and synthesis. Soon after, Ofele[31] and Wanzlick[32] reported the metal complexes
containing N-heterocycles for the first time. Unlike other metal complexes, it has an
electronic effect and a steric hindrance effect on a pair of lone electrons on NHC nitro-
gen and carbon atoms, which make the dissociation energy of the metal-carbon bond
between the metal and the N-heterocyclic carbene complex high, so the properties of
NHC are very stable. Since free N-heterocyclic carbene was successfully separated by
Arduengo[33] in 1991, the N-heterocyclic carbene palladium complex has attracted the
interest of many scientists and been researched extensively and deeply. In 1995,
Herrmann[34] reported for the first time the application of N-heterocyclic carbene and
its palladium complex in the Heck reaction, which greatly promoted the application of
N-heterocyclic carbene and its metal complex in the catalytic reaction.[35,36]
The use of N-heterocyclic carbenes (NHCs) as ligands has led to an array of exciting
developments in Pd-catalyzed cross-coupling reactions.[37,38] The high sensitivity of iso-
lated NHCs necessitates handling under rigorously anhydrous conditions.[37,39–41] In
situ preparation of active Pd–NHC catalysts has been the dominant strategy to

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SYNTHETIC COMMUNICATIONSV
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Scheme 2. Heck coupling reactions.
circumvent this problem.[42] Subsequently, the groups of Herrmann,[43,44] Nolan,[45–47]
Beller,[48] and Sigman[49] have published an array of monoligated Pd–NHC complexes
that show high levels of activity in Pd-catalyzed reactions. However, these catalysts were
all prepared under rigorous anhydrous conditions even when the isolated carbene was
not used. In 2006, Organ[50] developed a process for the preparation of Pd–NHC preca-
talysts in air, using readily available starting materials on a large scale in order to over-
come the strict synthesis conditions of Pd-NHC catalysts and the disadvantages of low
acceptance rate. Here, their group first reported the use of pyridine as a non-carbene
auxiliary ligand. Not only the good coordination ability of pyridine is used to stabilize
the Pd (II) complex, but also the advantage that pyridine is easy to leave and form an
empty coordination site to bind to the substrate is fully utilized.[51]
Influenced by the work of Organ[50] and coworkers, we also use pyridine as a non-
carbene ligand to synthesize NHC-Pd (II)-Py. At the same time, NHC’s good d-electron
donating properties and high basicity greatly enhance the catalytic activity of Pd (II)
complexes.[52] Inspired by these results, we report a method to synthesize a series of
stilbenes in high yields by forming carbon-carbon bonds between organic halides and
olefins under the condition of (0.01 eq) NHC-Pd (II)-Py. In addition, the reaction sys-
tem is so simple in operation, and various stilbene can be quickly and efficiently
obtained by large-scale experiments.
Results and discussion
The optimization procedure was carried out with Bromobenzene 1a and Styrene 2a as
model substrates for the NHC-Pd (II)-Py-catalyzed carbon-carbon cross-coupling. Some
representative results are shown in Table 1.
In our initial experiments, the Heck reaction of bromobenzene and styrene was carried
out with (0.15 eq) NHC-Pd(II)-Py, (0.5 eq) Cs2CO3 and (1.0mL) 1,4-dioxane at 100 ꢁC
for 12h. Gratifyingly, the reaction went smoothly and the expected product was obtained
in good yield under these conditions, (Table 1, entry 1). When KOtBu, KOH or K2CO3
was used as the base with other conditions unchanged (Table 1, entries 2, 3 and 4), the
reaction can achieve a moderate to good yield; When Et3N or 2,6-Lutidine was used as

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D. LI ET AL.
Table 1. Optimization for cross-coupling of Bromobenzene 1a and Styrene 2a by NHC-Pd (II)-Pya.
Entry
Cat (eq)
Base (eq)
Solvent
Temp (ꢁC)
Yield (%)b
1
2
3
4
5
6
7
8
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.01)
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.15)
NHC-Pd (II)-Py (0.05)
NHC-Pd (II)-Py (0.01)
NHC-Pd (II)-Py (0.01)
NHC-Pd (II)-Py (0.01)
NHC-Pd (II)-Py (0.01)
NHC-Pd (II)-Py (0.01)
NHC-Pd (II)-Py (0.01)
NHC-Pd (II)-Py (0.01)
PdCl2 (0.15)
Cs2CO3 (0.5)
KOtBu (0.5)
KOH (0.5)
K2CO3 (0.5)
Et3N (0.5)
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
DMF
THF
CH3CN
toluene
–
–
–
–
100
100
100
100
100
100
100
100
80
85
65
70
60
31
50
NRc
80
82
40
18
92
90
90
91
89
93
30
82
65
NRc
NRc
2,6-Lutidine (0.5)
–
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (1.0)
Cs2CO3 (3.0)
Cs2CO3 (0.3)
Cs2CO3 (0.1)
Cs2CO3 (0.3)
Cs2CO3 (0.3)
Cs2CO3 (0.3)
Cs2CO3 (0.3)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
80
100
100
100
100
100
100
100
100
130
70
–
–
–
–
–
1,4–Dioxane
100
100
–
–
aAll reactions were carried out with 1a (1 mmol), 2a(1.2 eq), cat (1.0–15 mol %), base (0.3–3 eq), solvent (1.0 mL) at
c
100 ꢁC for 12 h. bIsolated yields. No reaction.
the base, the yield of product 3a is low at 31% and 50%, respectively (Table 1, entries 5
and 6). Meanwhile, reaction was proved not to occur without base, which indicated that
anionic bases played a vital role in this system (Table 1, entry 7). Based on the results of
the previous screening, the influence of the solvent was then investigated. The reaction of
equivalent bromobenzene and styrene was conducted in solvent DMF, THF, toluene,
CH3CN respectively, and can get low to moderate yields (Table 1, entries 8–11).
However, the desired product can be obtained in good yield under solvent-free conditions
(Table 1, entry 12). Further investigation evidenced that the amount of NHC-Pd (II)-Py
was reduced from 0.15 eq to 0.1 eq, while the yield did not change (Table 1, entries
12–14). Next, increasing the amounts of Cs2CO3 from 0.5 eq to 3 eq, we found no sig-
nificant increase in yield (Table 1, entry 14–16). While decreasing the amounts of
Cs2CO3 to 0.1 eq, the yield of product 3a was significantly reduced (Table 1, entry 17
and 18). Interestingly, 0.3 eq Cs2CO3 was proved to be sufficient to provide excellent
yield of product 3a. Reducing the reaction temperature would extend the reaction time
(Table 1, entry 20) and cause the styrene to slowly polymerize, while using a higher tem-
perature was accelerated the polymerization of styrene, thereby reducing the yield (Table
1, entry 19). Thus, 100 ꢁC was chosen as most suitable temperature for the reaction sys-
tem. Meanwhile, reaction was proved not to occur when PdCl2 was used as catalyst
(Table 1, entry 21). Finally, the optimal condition of the reaction system was

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Table 2. NHC-Pd (II)-Py complex catalyzed reactions of aromatic bromides and olefins.
determined: 0.01 eq NHC-Pd (II)-Py and 0.3 eq Cs2CO3 were used for solvent-free reac-
tion at 100 ꢁC for 12hours, and the yield exceeded 90%.
Having established the optimized reaction conditions, we tested a variety of substi-
tuted aromatic bromine and olefin derivatives to probe the versatility of our catalytic
system, and the results are summarized in Table 2. Both bromobenzene and styrene
derivatives containing electron-donating groups and electron-withdrawing groups have
good tolerance in this reaction, and the corresponding stilbene is obtained in high yield
(>90%). To our delight, the reaction of different aromatic brominated derivatives with
styrene and its derivatives in the catalytic system also provides good yields. We found
that the reaction of 2-bromonaphthalene with 4-methylstyrene and styrene also pro-
ceeded very well, with very good yields of 97% and 98%, respectively (Table 2, 3j and
3k). Heterocyclic aromatic bromines are considered to be challenging substrates for

2046
D. LI ET AL.
Scheme 3. Reaction scale-up.
heck carbon-carbon cross-coupling.[53,54] However, the heteroaromatic substrate is also
compatible with the catalystic system, and reacts with styrene derivatives to produce the
corresponding products 3g, 3p, 3q with yields of 96%, 90% and 93%. In addition, the
corresponding product obtained from the reaction of 9-vinylanthracene and bromoben-
zene can also reach a yield of 96%. After proving the universality of aromatic bromides
and styrene in this method, the Heck reaction of aryl halide and tert-butyl acrylate can
also provide good yields in the same catalytic reaction system (Table 2, 3r, 3s, 3t
and 3u).
To demonstrate the utility of this method, resveratrol, which exerts anti-cancer,[55]
anti-bacterial,[56] and anti-fatigue effects,[56] was synthesized from 5-bromoresorcinol
and 4-hydrozystyrene in one step, and the yield is as high as 93% (Table 2).
In order to further prove the potential application of this NHC-Pd (II)-Py catalyzed
carbon-carbon coupling, we further illustrated its scalability. Under the conditions of
this catalytic system, the reaction of 1-bromo-4-nitrobenzene and styrene was used as a
scale-up reaction model. To our delight, under the conditions of this catalytic system,
when the reaction was scaled up to 49.5 mmol (1i, 10 g scale), the desired product 3i
was isolated in 88% yield (Scheme 3).
3. Conclusion
In summary, we have developed an efficient method for the Heck coupling of olefins
with various substituted aryl bromides by NHC-Pd (II)-Py under solvent-free condi-
tions. The presented synthetic methodology reveals excellent reactivity and good func-
tional group tolerance with moderate to excellent yields. The reaction system is so
simple and in operation that various stilbene can be obtained quickly and efficiently
and applied to the industry. Further extension of the application of the system to syn-
thesis of other bioactive molecules or important medical intermediates based on this
method is in progress in our laboratory.
4. Materials and methods
4.1. Chemicals and materials
Most of chemicals were purchased from Sigma-Aldrich, Strem, Acros, TCI or Alfa
1
Aesar and used as such unless stated otherwise. H and 13C NMR data were recorded
with Bruker Advance III (600 MHz) spectrometers with tetramethylsilane as an internal
standard. All chemical shifts (d) are reported in ppm and coupling constants (J) in Hz.
All chemical shifts were reported relative tetramethylsilane (0 ppm for 1H), CDCl3
1
(77.0 ppm for 13C) and DMSO-d6 (2.50 ppm for H, 39.50 ppm for 13C), respectively.

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Scheme 4. Synthesis of complexes NHC-Pd (II)-Py.
TLC plates were visualized by exposing UV light or by iodine. Purification of crude
compounds and separation of reaction mixtures were carried out by column chromatog-
raphy using silica gel (200–300 mesh, Shanghai, China). All substrates are known com-
pounds according to the literature.
4.2. General procedure for Heck Cross-Coupling reactions
To a single-necked flask (15 mL) equipped with a stir bar charge with 1 (1 eq, 1 mmol),
2 (1 eq, 1.2 mmol), NHC-Pd (II)-Py (0.01 eq, 0.06 g) and Cs2CO3 (0.3 eq, 0.1 g). Then
the reaction flask was stirred at 100 ꢁC for 12 h, and then the reaction mixture was
cooled to room temperature. After removing the solvent under reduced pressure, the
pure product was obtained by silica gel column chromatography (eluent: petroleum
ether/ethyl acetate).
The experimental operation of the amplification reaction is the same as the general
operation, but the work-up of the scale-up reaction is relatively convenient and simple.
After the reaction was completed, the reaction solution was filtered while hot, and the
filtrate was collected. The filtrate was frozen to ꢀ8 ꢁC until yellow crystals precipitated
out, and then filtered. After the filter cake is dried, the desired stilbene product
is obtained.
4.3. Preparation of the catalyst
i. A mixture of 2,6-diisopropylaniline (33.9 mmol) and HOAc (1.18 mmol) and
15 mL MeOH was stirred in at 50 ꢁC, then slowly dropwise added 15 mL of a
MeOH solution of glyoxal (40% aqueous solution, 16.7 mmol) in 15 minutes.
After the addition, the mixture continuing to stir at 50 ꢁC for 30 minutes and
then at room temperature for 10 hours. The reaction mixture was filtered dried
to obtain 5.6 g of yellow compound a[57] (87% yield).
ii. a (8.5 mmol) and paraformaldehyde (8.5 mmol) were added into 30 mL EtOAc
and stirred vigorously to dissolve at 70 ꢁC. Then, 20 mL of TMSCl (0.85 mmol)
in EtOAc was slowly added dropwise to the reaction flask within 20 minutes.
After reacting for 2 h, the reaction mixture is cooled to 10 ꢁC and filtered. The
filter cake was washed with EtOAc and dried to obtain 3.2 g of compound b[57]
as a white solid (89% yield).
iii. A mixture of b (2.84 mmol), PdCl2 (2.84 mmol), pyridine (2.84 mmol), K2CO3
(2.84 mmol) and THF (20 mL) were refluxed in a nitrogen atmosphere for about
24 hours. The product was purified by flash column chromatography to obtain
1.1 g yellow product c (NHC-Pd (II)-Py) (61% yield) (Scheme 4).[58]

2048
D. LI ET AL.
Figure 1. The X-ray crystal structure of c (NHC-Pd (II)-Py).
1
The structure of c (NHC-Pd (II)-Py) was established by the H and 13C NMR spec-
troscopic data (Supporting Information) and X-ray analysis. The X-ray crystal structure
of c is shown in Figure 1.
Supporting information
1
Full experimental detail, H and 13C NMR spectra, X-ray data. This material can be
found via the “Supplementary Content” section of this article’s webpage.
Acknowledgments
Thanks to the Pharmaceutical Design and Synthesis Laboratory and the Key Laboratory of
Biochemistry and Molecular Pharmacology of the School of Pharmacy of Chongqing Medical
University for improving the experimental platform and facilities.
Funding
The author is very grateful for the support of the Fundamental Research Fund of Chongqing
Science and Technology Commission [No.X0221].
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