Synthesis of chalcones via domino dehydrochlorination/Pd(OAc)2-catalyzed Heck reaction

Article abstract of DOI:10.1016/S1872-2067(14)60247-3

A new method has been developed for the cross-coupling of aryl halides with β-chloroalkyl aryl ketones and their ester and amide analogs through a domino dehydrochlorination/Pd(OAc)₂- catalyzed Heck reaction sequence. The enone intermediates generated in situ reduced the occurrence of side reactions and therefore enhanced the efficiency of the reaction. This reaction exhibited good tolerance to various functional groups on both substrates and provides rapid access to a wide range of chalcone derivatives.

Full text of DOI:10.1016/S1872-2067(14)60247-3

Chinese Journal of Catalysis 36 (2015) 78–85
ava i l a b l e a t w w w. s c i e n c ed i r e c t . c o m
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e /c h n j c
Article (Special Issue on Catalysis in Organic Synthesis)
Synthesis of chalcones via domino
dehydrochlorination/Pd(OAc)2‐catalyzed Heck reaction
Tenglong Guoa, Quanbin Jianga, Likun Yub, Zhengkun Yua,*
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China
b Fertilizer Analysis Station of Technology Center, SINOPEC Baling Petrochemical Company, Yueyang 414003, Hunan, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A new method has been developed for the cross‐coupling of aryl halides with β‐chloroalkyl aryl
ketones and their ester and amide analogs through a domino dehydrochlorination/Pd(OAc)2‐cata‐
lyzed Heck reaction sequence. The enone intermediates generated in situ reduced the occurrence of
side reactions and therefore enhanced the efficiency of the reaction. This reaction exhibited good
tolerance to various functional groups on both substrates and provides rapid access to a wide range
of chalcone derivatives.
Received: 22 August 2014
Accepted 22 September 2014
Published 20 January 2015
Keywords:
© 2015, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
β‐Chloroalkyl aryl ketone
Heck reaction
Enone
Domino reaction
Chalcone
1. Introduction
methods for the arylation and vinylation of alkenes [14]. Alt‐
hough chalcones can be generated directly by the Heck‐type
Chalcones are an important class of biologically active com‐
pounds (Scheme 1) [1,2], which have been reported to exhibit a
wide range of pharmacological properties, including anticancer,
anti‐inflammatory, antioxidant, antimicrobial, and antiallergic
activity [3]. Compounds belonging to this structural class are
also recognized as important intermediates for the synthesis of
heterocyclic systems [4–6] and functional materials [7,8].
Chalcones are generally synthesized using a Claisen‐Schmidt
condensation [9]. However, the overall efficiency and function‐
al group tolerance of this reaction are usually poor because of
its requirement for strongly basic conditions. To overcome
these limitations, several transition‐mental‐catalyzed cross‐
coupling reactions have been developed for the synthesis of
chalcones, which can be conducted under relatively mild condi‐
tions [10–13].
cross‐coupling of aryl halides with aryl vinyl ketones, there
have been very few examples of this reaction in the literature
[15,16]. The main reason for the lack of publications in this
area can be attributed to the poor stability of most aryl vinyl
ketones (enones), which can decompose upon exposure to
heat, light and oxygen during their preparation and storage.
Multi‐step procedures are therefore often required for the
preparation of α,β‐unsaturated carbonyl compounds starting
from the corresponding saturated carbonyl compounds
[17,18]. For the synthesis of chalcones using enones as sub‐
strates, it is envisaged that a domino reaction sequence involv‐
ing the in‐situ generation of an enone followed by its cross‐
coupling with an aryl halide would provide facile access to a
broad range of chalcones. The Pd‐catalyzed cross‐coupling
reactions of propiophenones with aryl carboxylic acids [19]
and (hetero)arenes [20] have been reported to afford chalcon‐
The Pd‐catalyzed Heck reaction is one of the most powerful
* Corresponding author. Tel/Fax: +86‐411‐8437 9227; E‐mail: zkyu@dicp.ac.cn
This work was supported by the National Natural Science Foundation of China (21272232).
DOI: 10.1016/S1872‐2067(14)60247‐3 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 36, No. 1, January 2015

Tenglong Guo et al. / Chinese Journal of Catalysis 36 (2015) 78–85
79
HO2C
O
O
O
O
Ph
O
OH
HO
O
HO
O
O
OH
OH
O
O
O
O
HO
OH
OH
OH
sofalcone
metochalcone
butein
rottlerin
Scheme 1. Examples of bioactive chalcones.
es via the in‐situ generation of the corresponding enones. The
decarboxylative arylation of benzoylacrylic acids has also been
reported to provide access to chalcones in a similar manner
[21]. Although these methods represent useful strategies for
the synthesis of chalcones, their overall utility has been limited
by their general requirement for high loadings of the catalysts
and oxidants under relatively harsh conditions. We recently
found that β‐chloroalkyl aryl ketones and their ester and amide
analogs could be used as precursors to α,β‐unsaturated car‐
bonyls in the Rh(I)‐catalyzed conjugate addition by arylboronic
acids [22], as well as the Pd‐catalyzed, Cu‐mediated synthesis
of carbazoles [23]. As part of our ongoing research into the
development of new domino reactions [24], we envisioned that
in‐situ generated enones could be employed in a Heck‐type
cross‐coupling reaction under mild conditions without the ad‐
dition of an oxidant. Herein, we report the development of a
new method for the synthesis of chalcones by Pd‐catalyzed
formal sp2 C‐X (X = I, Br) / sp3 C‐Cl cross‐coupling of aryl halides
with β‐chloroalkyl aryl ketones, and their ester and amide ana‐
logs.
rinsed with DCM (5 mL), and the combined filtrates were
washed with brine (15 mL), dried over anhydrous Na2SO4. The
solvent was then removed under reduced pressure to give the
crude product as a residue, which was purified by silica gel
column chromatography eluting with a mixture of petroleum
ether (60–90 °C)/EtOAc (v/v = 30:1).
1
(E)‐Chalcone (3a) [21]. Yield 90%, pale yellow solid. H
NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 7.3 Hz, 2H, aromatic CH),
7.90 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.72 (dd, J = 6.3, 2.8 Hz,
2H, aromatic CH), 7.69–7.55 (m, 4H, aromatic CH and
CH=CHCOPh), 7.52–7.46 (m, 3H, aromatic CH).
(E)‐1‐Phenyl‐3‐(p‐tolyl)prop‐2‐en‐1‐one (3b) [21]. Yield
83%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ =
8.07–7.99 (m, 2H, aromatic CH), 7.80 (d, J = 15.7 Hz, 1H,
CH=CHCOPh), 7.61–7.46 (m, 6H, aromatic CH and
CH=CHCOPh), 7.24 (t, J = X Hz, 2H, aromatic CH), 2.40 (s, 3H,
CH3).
(E)‐1‐phenyl‐3‐(m‐tolyl)prop‐2‐en‐1‐one (3c) [21]. Yield
84%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J
= 7.4 Hz, 2H, aromatic CH), 7.85 (d, J = 15.7 Hz, 1H,
CH=CHCOPh), 7.58 (m, 4H, aromatic CH and CH=CHCOPh), 7.49
(d, J = 6.0 Hz, 2H, aromatic CH), 7.35 (t, 1H, aromatic CH), 7.28
(t, 1H, aromatic CH), 2.44 (s, 3H, CH3).
2. Experimental
General considerations. All the aryl halides were purchased
from commercial suppliers and used as provided without fur‐
ther purification. The β‐chloroalkyl carbonyl compounds were
either purchased from commercial suppliers or prepared ac‐
cording to the literature procedures [22]. Compounds 3a–3c
[21], 3d [25], 3e and 3f [21], 3g [26], 3h [21], 3i [25], 3j [21],
3k [27], 3l [27], 3m [21], 3n [28], 5a and 5b [10], 5c [29], 5d
[30], 5e [31], 5f and 5g [10], 5h and 5i [25], 5j [32], 5k [33], 5l
[34], and 5m and 5n [35] are known compounds and the spec‐
troscopic features of the materials synthesized in current study
were found to be in good agreement with those reported in the
literature. All of the solvents used in the current study were
freshly distilled prior to use. 1H and 13C NMR spectra were rec‐
orded on a Bruker DRX‐400 spectrometer (Bruker, German)
and all the chemical shift values were measured relative to
tetramethylsilane (TMS; TMS = 0.00) or the residual chloroform
peak of CDCl3 [ (1H) = 7.26;  (13C) = 77.16].
General procedure for the synthesis of chalcones  synthesis
of chalcone 3a. A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol),
PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4
mmol), 3‐chloropropiophenone (2a) (87 mg, 0.5 mmol), and
K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a
N2 atmosphere at room temperature for 10 min, and then
heated at 90 °C for 16 h. The reaction was then cooled to am‐
bient temperature and diluted with CH2Cl2 (10 mL) before be‐
ing filtered through a short pad of silica gel. The silica pad was
(E)‐1‐Phenyl‐3‐(o‐tolyl)prop‐2‐en‐1‐one (3d) [25]. Yield
87%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J
= 15.6 Hz, 1H, CH=CHCOPh), 8.08 (m, 2H, aromatic CH), 7.75 (d,
J = 7.4 Hz, 1H, aromatic CH), 7.63 (t, J = X Hz, 1H, aromatic CH),
7.53 (m, 3H, aromatic CH and CH=CHCOPh), 7.35 (t, 1H, aro‐
matic CH), 7.28 (m, 2H, aromatic CH), 2.52 (s, 3H, CH3).
(E)‐3‐(4‐Methoxyphenyl)‐1‐phenylprop‐2‐en‐1‐one (3e)
[21]. Yield 85%, white solid. 1H NMR (400 MHz, CDCl3): δ = 8.01
(d, J = 8.1 Hz, 2H, aromatic CH), 7.79 (d, J = 15.6 Hz, 1H,
CH=CHCOPh), 7.59 (m, 3H, aromatic CH), 7.50 (t, J = X Hz, 2H,
aromatic CH), 7.42 (d, J = 15.6 Hz, 1H, CH=CHCOPh), 6.94 (d, J =
8.5 Hz, 2H, aromatic CH), 3.86 (s, 3H, OCH3).
(E)‐3‐(4‐Chlorophenyl)‐1‐phenylprop‐2‐en‐1‐one (3f)
[21]. Yield 86%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ
= 8.00 (m, 2H, aromatic CH), 7.74 (d, J = 15.7 Hz, 1H,
CH=CHCOPh), 7.57 (m, 3H, aromatic CH), 7.49 (m, 3H, aromatic
CH and CH=CHCOPh), 7.37 (d, J = 8.5 Hz, 2H, aromatic CH).
(E)‐3‐(2‐Chlorophenyl)‐1‐phenylprop‐2‐en‐1‐one (3g)
[26]. Yield 81%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ
= 8.19 (d, J = 15.8 Hz, 1H, CH=CHCOPh), 8.02 (d, J = 7.2 Hz, 2H,
aromatic CH), 7.75 (dd, J = 7.0, 2.4 Hz, 1H, aromatic CH), 7.59 (t,
J = X Hz, 1H, aromatic CH), 7.50 (m, 3H, aromatic CH and
CH=CHCOPh), 7.43 (m, 1H, aromatic CH), 7.32 (m, 2H, aromatic
CH).
(E)‐3‐(4‐fluorophenyl)‐1‐phenylprop‐2‐en‐1‐one (3h)
[21]. Yield 91%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ

80
Tenglong Guo et al. / Chinese Journal of Catalysis 36 (2015) 78–85
= 8.02 (d, J = 7.3 Hz, 2H, aromatic CH), 7.77 (d, J = 15.7 Hz, 1H,
CH=CHCOPh), 7.66–7.56 (m, 3H, aromatic CH), 7.49 (m, 3H,
aromatic CH and CH=CHCOPh), 7.10 (t, 2H, aromatic CH).
(E)‐1‐Phenyl‐3‐(4‐(trifluoromethyl)phenyl)prop‐2‐en‐1
‐one (3i) [25]. Yield 80%, pale yellow solid. 1H NMR (400 MHz,
CDCl3): δ = 8.03 (d, J = 7.6 Hz, 2H, aromatic CH), 7.80 (d, J = 15.7
Hz, 1H, CH=CHCOPh), 7.73 (d, J = 8.1 Hz, 2H, aromatic CH), 7.66
(d, J = 8.1 Hz, 2H, aromatic CH), 7.60 (m, 2 H, aromatic CH and
CH=CHCOPh), 7.51 (t, J = 7.5 Hz, 2H, aromatic CH).
= 3.8 Hz, 6H, 2×CH3).
(E)‐1‐(2,4‐Dimethylphenyl)‐3‐phenylprop‐2‐en‐1‐one
(5d) [30]. Yield 84%, pale yellow solid. H NMR (400 MHz,
CDCl3): δ = 7.57 (m, 2H, aromatic CH), 7.52 (d, J = 16.0 Hz, 1H,
CH=CHCOPh), 7.47 (d, J = 7.6 Hz, 1H, aromatic CH), 7.40 (m, 3H,
aromatic CH), 7.19 (d, J = 16.0 Hz, 1H, CH=CHCOPh), 7.10 (d, J =
9.1 Hz, 2H, aromatic CH), 2.46 (s, 3H, CH3), 2.39 (s, 3H, CH3).
(E)‐1‐(2,5‐Dimethylphenyl)‐3‐phenylprop‐2‐en‐1‐one
1
1
(5e) [31]. Yield 82%, pale yellow solid. H NMR (400 MHz,
(E)‐Methyl 4‐(3‐oxo‐3‐phenylprop‐1‐en‐1‐yl)benzoate
(3j) [21]. Yield 79%, pale yellow solid. 1H NMR (400 MHz,
CDCl3): δ = 8.08–7.98 (m, 4 H, aromatic CH), 7.79 (d, J = 15.7,
1H, CH=CHCOPh), 7.67 (dd, J = 8.3, 1.8 Hz, 2H, aromatic CH),
7.62–7.55 (m, 2H, aromatic CH and CH=CHCOPh), 7.49 (m, 2H,
aromatic CH), 3.92 (s, 3H, CO2CH3).
(E)‐4‐(3‐Oxo‐3‐phenylprop‐1‐en‐1‐yl)benzonitrile (3k)
[27]. Yield 70%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ
= 8.01 (d, J = 7.4 Hz, 2H, aromatic CH), 7.78–7.70 (m, 3H, aro‐
matic CH and CH=CHCOPh), 7.68 (d, J = 8.6 Hz, 2H, aromatic
CH), 7.64–7.57 (m, 2H, aromatic CH and CH=CHCOPh), 7.51 (t,
2H, aromatic CH).
CDCl3): δ = 7.58 (m, 2H, aromatic CH), 7.48 (d, J = 16.1 Hz, 1H,
CH=CHCOPh), 7.40 (m, 3H, aromatic CH), 7.31 (s, 1H, aromatic
CH), 7.22–7.12 (m, 3H, aromatic CH and CH=CHCOPh), 2.41 (s,
3H, CH3), 2.38 (s, 3H, CH3).
(E)‐1‐(4‐Chlorophenyl)‐3‐phenylprop‐2‐en‐1‐one (5f)
[10]. Yield 86%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ
= 7.96 (d, J = 8.4 Hz, 2H, aromatic CH), 7.81 (d, J = 15.7 Hz, 1H,
CH=CHCOPh), 7.64 (m, 2H, aromatic CH), 7.47 (m, 3H, aromatic
CH and CH=CHCOPh), 7.41 (m, 3H, aromatic CH).
(E)‐1‐(4‐Fluorophenyl)‐3‐phenylprop‐2‐en‐1‐one (5g)
[10]. Yield 90%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ
= 8.06 (dd, J = 8.7, 5.5 Hz, 2H, aromatic CH), 7.82 (d, J = 15.7 Hz,
1H, CH=CHCOPh), 7.64 (m, 2H, aromatic CH), 7.51 (d, J = 15.7
Hz, 1H, CH=CHCOPh), 7.46–7.37 (m, 3H, aromatic CH), 7.17 (t, J
= X Hz, 2H, aromatic CH).
(E)‐3‐(4‐Nitrophenyl)‐1‐phenylprop‐2‐en‐1‐one
(3l)
1
[27]. Yield 58%, yellow solid. H NMR (400 MHz, CDCl3): δ =
8.28 (d, J = 8.7 Hz, 2H, aromatic CH), 8.04 (d, J = 7.3 Hz, 2H, ar‐
omatic CH), 7.81 (m, 3H, aromatic CH and CH=CHCOPh), 7.64
(m, 2H, aromatic CH and CH=CHCOPh), 7.53 (t, J = 7.6 Hz, 2H,
aromatic CH).
(E)‐3‐Phenyl‐1‐(thiophen‐2‐yl)prop‐2‐en‐1‐one
(5h)
1
[25]. Yield 80%, yellow solid. H NMR (400 MHz, CDCl3): δ =
7.90–7.81 (m, 2H, thienyl CH and CH=CHCOPh), 7.70–7.60 (m,
3H, thienyl CH and aromatic CH), 7.40 (m, 4H, aromatic CH and
CH=CHCOPh), 7.18 (t, J = 4.2 Hz, 1H, thienyl CH).
(E)‐3‐(4‐Acetylphenyl)‐1‐phenylprop‐2‐en‐1‐one (3m)
1
[21]. Yield 51%, yellow solid. H NMR (400 MHz, CDCl3): δ =
8.01 (m, 4 H, aromatic CH), 7.80 (d, J = 15.8 Hz, 1H,
CH=CHCOPh), 7.71 (d, J = 8.4 Hz, 2H, aromatic CH), 7.64–7.56
(m, 2H, aromatic CH and CH=CHCOPh), 7.50 (m, 2H, aromatic
CH), 2.62 (s, 3H, CH3).
(E)‐1‐(Furan‐2‐yl)‐3‐phenylprop‐2‐en‐1‐one (5i) [25].
Yield 78%, yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J
= 15.8 Hz, 1H, CH=CHCOPh), 7.63 (m, 3H, furyl CH and aromatic
CH), 7.49–7.37 (m, 4H, aromatic CH and CH=CHCOPh), 7.32 (d, J
= 3.3 Hz, 1H, furyl CH), 6.57 (dd, J = 3.4 and 1.5 Hz, 1H, furyl
CH).
(E)‐1‐Phenyl‐3‐(thiophen‐2‐yl)prop‐2‐en‐1‐one
(3n)
1
[28]. Yield 75%, yellow solid. H NMR (400 MHz, CDCl3): δ =
8.00 (d, J = 7.6 Hz, 2H, aromatic CH), 7.94 (d, J = 15.3 Hz, 1H,
CH=CHCOPh), 7.57 (t, J = X Hz, 1H, aromatic CH), 7.49 (t, J = X
Hz, 2H, aromatic CH), 7.41 (d, J = 5.0 Hz, 1H, thienyl CH),
7.37–7.30 (m, 2H, thienyl CH and CH=CHCOPh), 7.11–7.03 (m, 1
H, thienyl CH).
(E)‐1‐(1‐Methyl‐1H‐indol‐3‐yl)‐3‐phenylprop‐2‐en‐1‐on
e (5j) [32]. Yield 85%, white solid. 1H NMR (400 MHz, CDCl3): δ
= 8.54 (dd, J = 6.5, 2.3 Hz, 1H, indolyl CH), 7.80 (d, J = 15.6 Hz,
1H, CH=CHCOPh), 7.75 (d, J = 2.6 Hz, 1H, indolyl CH), 7.61 (d, J =
7.3 Hz, 2H, aromatic CH), 7.38 (m, 3H, aromatic CH), 7.34–7.25
(m, 4H, aromatic CH and CH=CHCOPh), 3.77 (s, 3H, NCH3).
(E)‐3‐Phenyl‐1‐(p‐tolyl)prop‐2‐en‐1‐one (5a) [10]. Yield
83%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J
= 8.2 Hz, 2H aromatic CH), 7.82 (d, J = 15.7 Hz, 1H,
CH=CHCOPh), 7.64 (m, 2H, aromatic CH), 7.55 (d, J = 15.7 Hz,
1H, CH=CHCOPh), 7.41 (m, 3H, aromatic CH), 7.30 (d, J = 8.1 Hz,
2H, aromatic CH), 2.43 (s, 3H, CH3).
(E)‐1‐(4‐Methoxyphenyl)‐3‐phenylprop‐2‐en‐1‐one
(5b) [10]. Yield 89%, white solid. 1H NMR (400 MHz, CDCl3): δ
= 8.04 (d, J = 8.8 Hz, 2H, aromatic CH), 7.80 (d, J = 15.7 Hz, 1H,
CH=CHCOPh), 7.63 (m, 2H, aromatic CH), 7.55 (d, J = 15.6 Hz,
1H, CH=CHCOPh), 7.40 (m, 3H, aromatic CH), 6.97 (d, J = 8.8 Hz,
2H, aromatic CH), 3.86 (s, 3H, OCH3).
(E)‐1‐(3,4‐Dimethylphenyl)‐3‐phenylprop‐2‐en‐1‐one
(5c) [29]. Yield 83%, white solid. 1H NMR (400 MHz, CDCl3): δ =
7.80 (m, 3H, aromatic CH and CH=CHCOPh), 7.65 (m, 2H, aro‐
matic CH), 7.55 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.46–7.39 (m,
3H, aromatic CH), 7.26 (d, J = 7.8 Hz, 1H, aromatic CH), 2.35 (d, J
1
m‐Tolyl cinnamate (5k) [33]. Yield 79%, white solid. H
NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 16.0 Hz, 1H,
CH=CHCOOPh), 7.66–7.55 (m, 2H, aromatic CH), 7.44 (m, 3H,
aromatic CH), 7.31 (t, J = 7.7 Hz, 1H, aromatic CH), 7.09 (d, J =
7.6 Hz, 1H, aromatic CH), 7.01 (d, J = 8.6 Hz, 2H, aromatic CH),
6.66 (d, J = 16.0 Hz, 1H, CH=CHCOOPh), 2.40 (s, 3H, CH3).
4‐Chlorophenyl cinnamate (5l) [34]. Yield 77%, white
1
solid. H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 16.0 Hz, 1H,
CH=CHCOOPh), 7.60 (m, 2H, aromatic CH), 7.45 (m, 3H, aro‐
matic CH), 7.38 (d, J = 8.8 Hz, 2H, aromatic CH), 7.14 (d, J = 8.8
Hz, 2H, aromatic CH), 6.63 (d, J = 16.0 Hz, 1H, CH=CHCOOPh).
N‐Methyl‐N‐(p‐tolyl)cinnamamide (5m) [35]. Yield 90%,
white solid. 1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 15.6 Hz,
1H, CH=CHCONAr), 7.29 (m, 5H), 7.22 (d, J = 8.0 Hz, 2H, aro‐
matic CH), 7.10 (d, J = 8.1 Hz, 2H, aromatic CH), 6.39 (d, J = 15.6
Hz, 1H, CH=CHCONAr), 3.38 (s, 3H, NCH3), 2.40 (s, 3H, CH3).

Tenglong Guo et al. / Chinese Journal of Catalysis 36 (2015) 78–85
81
N‐(4‐Chlorophenyl)‐N‐methylcinnamamide (5n) [35].
Table 1
Yield 88%, white solid. 1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J
= 15.5 Hz, 1H, CH=CHCONAr), 7.41 (d, J = 7.5 Hz, 2H, aromatic
CH), 7.32 (m, 5H, aromatic CH), 7.18 (d, J = 7.5 Hz, 2H, aromatic
CH), 6.35 (d, J = 15.5 Hz, 1H, CH=CHCONAr), 3.39 (s, 3H, NCH3).
Screening of conditions for the reaction of 1a with 2a.
Entry
1
2
3
4
5
6
7
8
Solvent
Dioxane
CH3CN
DMF
DMSO
PhCH3
H2O
DMF
DMF
DMF
DMF
Base
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Na2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
Yield a (%)
3. Results and discussion
74
83
90 (78) b
65
40
60
90 b
78
0
83
97 (90) b
95 e
3.1. Optimization of the reaction conditions
The reaction of iodobenzene (1a) with a single equivalent of
3‐chloropropiophenone (2a) was selected as a model reaction
for the optimization of the reaction conditions. The model reac‐
tion was initially conducted in dioxane at 90 °C under a N2 at‐
mosphere using 5 mol% Pd(OAc)2 as the catalyst, 10 mol%
PPh3 as the ligand, and K3PO4 as the base, which gave the de‐
sired chalcone product 3a in a GC yield of 74% (Table 1, entry
1). Several other solvents were screened in the reaction, in‐
cluding MeCN, DMF, DMSO, PhCH3 and H2O, and DMF was
found to provide the best results in terms of the yield of the
chalcone product 3a (Table 1, entries 2–6). It is noteworthy
9
10 c
11 c
12 d
DMF
DMF
Reaction conditions: 1a (0.4 mmol), 2a (0.4 mmol), Pd(OAc)2 (5 mol%),
PPh3 (10 mol%), and base (1.2 mmol) in solvent (2.5 mL) at 90 C for 16
h under 0.1 MPa of N2. a GC yield using mesitylene as an internal stand‐
ard. b Isolated yield in parentheses. c 2a (0.5 mmol). d 1a (0.5 mmol) and
2a (0.4 mmol). e Yield based on 2a.
Table 2
Reactions of aryl halides with 2a.
Aryl
Halide (1)
Isolated
yield (%)
90
Aryl
Halide(1)
Isolated
yield (%)
80
Entry
1
Product (3)
Entry
9
Product(3)
1a
1b
1i
3a
3i
2
83
10
79
1j
3b
3j
3
4
84
87
11
12
70
58
1k
1c
3c
3k
1l
1m
1n
3d
1d
1e
3l
5
6
85
86
13
14
51
75
3e
3f
3m
1f
3n
7
8
81
91
15
16
33
0
1o
1p
3g
3h
3a
3a
1g
1h
Reaction conditions: 1 (0.4 mmol), 2a (0.5 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), and K2CO3 (1.2 mmol) in DMF (2.5 mL) at 90 C for 16 h
under 0.1 MPa of N2.

82
Tenglong Guo et al. / Chinese Journal of Catalysis 36 (2015) 78–85
that the reaction proceeded smoothly in H2O to form 3a in
moderate yield (Table 1, entry 6). Having identified the opti‐
mum solvent, we proceeded to screen a series of different ba‐
ses, including K2CO3, Na2CO3 and Cs2CO3 (Table 1, entries
7–10). Interestingly, K3PO4 and K2CO3 both worked more effi‐
ciently than Na2CO3, whereas the use of the stronger base
Cs2CO3 failed to provide any of the desired products (Table 1,
entry 9). Increasing the loading of 2a to 1.25 equiv. led to an
increase in the isolated yield to 90% when K2CO3 was used as
the base (Table 1, entry 11). In contrast, increasing the loading
of 1a to 1.25 equiv. led to a slight decrease in the yield (Table 1,
entry 12).
3.2. Substrate scope
With the optimized conditions in hand, we proceeded to
evaluate the scope of the reaction using a series of aryl halides
(Table 2). Pleasingly, aryl iodides bearing an electron‐donating
group such as a methyl or methoxy group reacted smoothly
with 2a to give the desired products 3b–3e in 83%–87% yields
(Table 2, entries 2–5). Furthermore, compound 2a reacted with
4‐, 3‐ and 2‐iodotoluene to give the corresponding products in
similar high yields, showing no obvious steric effect (Table 2,
entries 2–4). Aryl iodides bearing weakly electron‐withdrawing
groups also reacted smoothly with 2a to afford the corre‐
sponding chalcone products 3f–3j in good to excellent yields
(Table 2, entries 6–10). However, highly electron‐deficient aryl
iodides, such as 1k–1m, exhibited much lower levels of reactiv‐
ity to give 3k–3m in moderate yields (Table 2, entries 11–13).
Notably, only trace amounts of 4, formed from the dimeriza‐
tion of the in‐situ generated enone—that is, the phenyl vinyl
ketone from the dehydrochlorination of 2a—were detected
during the optimization of this reaction.
Table 3
Reactions of β‐chloroalkyl carbonyl compounds with 1a.
Isolated
yield (%)
83
β‐Chloroalkyl carbonyl
(2)
Isolated
yield (%)
80
Entry β‐Chloroalkyl carbonyl (2)
Product (5)
Entry
8
Product (5)
O
1
Me
2i
2j
2b
5h
5i
5a
5b
5c
2
89
83
9
78
85
2c
3
10
2d
2k
2l
5j
4
84
82
11
12
79
77
5d
2e
5k
5
2m
5l
2f
5e
5f
6
86
90
13
14
90
88
2n
2o
2g
5m
5n
7
2h
5g
Reaction conditions: 1 (0.4 mmol), 2a (0.5 mmol), Pd(OAc)2 (5 mol%), PPh3 (10 mol%), and K2CO3 (1.2 mmol) in DMF (2.5 mL) at 90 C for 16 h under
0.1 MPa of N2.

Tenglong Guo et al. / Chinese Journal of Catalysis 36 (2015) 78–85
83
2‐Iodothiophene also reacted smoothly under the optimized
conditions to give 3n in 75% yield (Table 2, entry 14). Although
aryl iodides reacted efficiently with 2a to give the correspond‐
ing chalcones, bromobenzene reacted slowly to form 3a in 33%
yield (Table 2, entry 15). Furthermore, chlorobenzene failed to
provide any of the desired product under the optimized condi‐
tions (Table 2, entry 16).
The scope of the β‐chloroalkyl carbonyl compounds was al‐
so explored by reacting a series of these compounds with io‐
dobenzene (1a) under the optimized conditions (Table 3). The
reactions of substituted 3‐chloropropiophenones 2b–2h pro‐
ceeded efficiently to afford the desired products 5a–5g in
82%–89% yields, with good functional group tolerance exhib‐
ited towards methyl, methoxy, chloro, and fluoro substituents
on the phenyl ring (Table 3, entries 1–7). The corresponding
thienyl, furyl, and indolyl derivatives of type 2 also exhibited
good reactivity to give the corresponding products 5h–5j in
78–85% yields (Table 3, entries 8–10). Pleasingly, the ester and
amide substrates 2l–2o also reacted smoothly under the opti‐
mized conditions to furnish 5k–5n (77%–90%), with the esters
reacting more efficiently than the amides (Table 3, entries
11–14).
Competition reactions were performed to determine the
reactivity of the different substrates. An equimolar mixture of
1b and 1f was reacted with 2a to give a mixture of 3b/3f
(mol/mol = 39:61; Eq. (1)), revealing that the presence of an
electron‐withdrawing substituent on the phenyl ring of the aryl
iodide substrate provided a higher yield of the corresponding
chalcone than the corresponding reaction with an elec‐
tron‐donating group. Treatment of 1a with an equimolar mix‐
ture of 2b and 2g under the same conditions led to a mixture of
5a and 5f (mol/mo = 41:59; Eq. (2)), demonstrating that an
electron‐withdrawing substituent on the aryl moiety of the
β‐chloroalkyl aryl ketone provided a higher yield of the corre‐
sponding chalcone than the corresponding reaction with an
electron‐donating group.
Scheme 2. A proposed mechanism for the reaction of 1a with 2a.
It has been confirmed that heating substrates such as 2 un‐
der basic conditions leads to formation of the corresponding
enones [22,23]. Interestingly, the reaction of phenyl vinyl ke‐
tone (6) with 1a under conditions similar to those developed in
this study afforded 3a in 92% isolated yield (Eq. (3)), which
suggested that enones such as 6 were being generated in situ
from 2, and that enones could therefore be acting as interme‐
diates in the current coupling reactions of 1 with 2.
Based on the results of this study, we have proposed a
mechanism for this transformation, which is depicted in
Scheme 2 for the reaction of 1a with 2a. Briefly, Pd(OAc)2
would be reduced by PPh3 to give a Pd(0) species, which would
initiate the catalytic reaction. Oxidative addition of PhI to Pd(0)
would lead to the formation of species A, which would react
with enone 6 (generated in‐situ from 2a) to produce π‐complex
B. Enone 6 would then undergo alkene insertion into the Pd‐C
bond to yield C, followed by β‐hydride elimination to produce
product 3a and the Pd(II) species D. The Pd(0) species would
then be regenerated by the reductive elimination of HI from D
in the presence of K2CO3 to complete the catalytic cycle.
3.3. Mechanism
5 mol% Pd(OAc)2
10 mol% PPh3
O
O
I
I
O
+
+
Ph
Ph
+
K2CO3 (3.0 equiv)
DMF, 90 oC, 16 h
100%
Ph
Cl
Me
(1)
(2)
Cl
Me
Cl
1b
1f
2a
3b
3f
0.4 mmol
0.4 mmol
0.5 mmol
3b : 3f = 39 : 61
O
O
O
O
5 mol% Pd(OAc)2
10 mol% PPh3
Cl
Cl
Ph
+
Ph
+
+
PhI
K2CO3 (3.0 equiv)
DMF, 90 oC, 16 h
100%
Me
Cl
Me
Cl
5a
5f
1a
0.4 mmol
2b
2g
0.5 mmol
0.5 mmol
5a : 5f = 41 : 59

84
Tenglong Guo et al. / Chinese Journal of Catalysis 36 (2015) 78–85
Graphical Abstract
Chin. J. Catal., 2015, 36: 78–85 doi: 10.1016/S1872‐2067(14)60247‐3
Synthesis of chalcones via domino dehydrochlorination/
Pd(OAc)2‐catalyzed Heck reaction
Tenglong Guo, Quanbin Jiang, Likun Yu, Zhengkun Yu*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences;
SINOPEC Baling Petrochemical Company
Efficient cross‐coupling of aryl halides with β‐chloroalkyl aryl ketones and their
ester and amide analogs through
a novel domino dehydrochlorina‐
tion/Pd(OAc)2‐catalyzed Heck reaction has been developed. The new strategy
uses in‐situ generated enones as the reaction intermediates to reduce the oc‐
currence of side reactions and enhance the reaction efficiency. This new pro‐
tocol represents a concise method for the synthesis of chalcones.
[16] Bianco A, Cavarischia C, Guiso M. Eur J Org Chem, 2004: 2894
4. Conclusions
[17] Yu J Q, Wu H C, Corey E J. Org Lett, 2005, 7: 1415.
[18] Uyanik M, Akakura M, Ishihara K. J Am Chem Soc, 2009, 131: 251
[19] Zhou J, Wu G, Zhang M, Jie X M, Su W P. Chem Eur J, 2012, 18:
8032
[20] Shang Y P, Jie X M, Zhou J, Hu P, Huang S J, Su W P. Angew Chem Int
Ed, 2013, 52: 1299
[21] Unoh Y, Hirano K, Satoh T, Miura M. J Org Chem, 2013, 78: 5096
[22] Jiang Q B, Guo T L, Wang Q F, Wu P, Yu Z K. Adv Synth Catal, 2013,
355: 1874
In summary, a new reaction for the cross‐coupling of aryl
halides with β‐chloroalkyl aryl ketones and their ester and am‐
ide analogs has been developed involving a domino dehydro‐
chlorination/Pd(OAc)2‐catalyzed Heck reaction with in‐situ
generated enones acting as the reaction intermediates. This
new method provides rapid access to chalcones from readily
available starting materials.
[23] Guo T L, Jiang Q B, Huang F, Chen J P, Yu Z K. Org Chem Front,
2014, 1: 707
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