Palladium-Catalyzed One-Pot Four-Component Synthesis of β-Cyano-α,β-unsaturated Ketones Using Calcium Carbide as an Acetylene Source and Potassium Hexacyanoferrate(II) as an Eco-Friendly Cyanide Source

Article abstract of DOI:10.1002/adsc.201900733

Palladium-catalyzed one-pot four-component synthesis of β-cyano-α,β-unsaturated ketones by the reactions of aryl halides, calcium carbide, potassium hexacyanoferrate(II) and aroyl chlorides is described. The salient features of this protocol are the direct use of easy-to-handle acetylene source and eco-friendly cyanide source, wide scope of substrates with good functional group tolerance, and simple work-up procedure. (Figure presented.).

Full text of DOI:10.1002/adsc.201900733

Title: Palladium-Catalyzed One-Pot Four-Component Synthesis of β-
Cyano-α,β-unsaturated Ketones Using Calcium Carbide as an
Acetylene Source and Potassium Hexacyanoferrate(II) as an
Eco-Friendly Cyanide Source
Authors: Hao Lu and Zheng Li
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900733
Link to VoR: http://dx.doi.org/10.1002/adsc.201900733

10.1002/adsc.201900733
Advanced Synthesis & Catalysis
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed One-Pot Four-Component Synthesis of β-
Cyano-α,β-unsaturated Ketones Using Calcium Carbide as an
Acetylene Source and Potassium Hexacyanoferrate(II) as an
Eco-Friendly Cyanide Source
Hao Lua, Zheng Lia*
a
Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu, 730070, P. R. China.
E-mail: lizheng@nwnu.edu.cn.
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: Palladium-catalyzed one-pot four-component
synthesis of β-cyano-α,β-unsaturated ketones by the
reactions of aryl halides, calcium carbide, potassium
hexacyanoferrate(II) and aroyl chlorides is described. The
salient features of this protocol are the direct use of easy-to-
handle acetylene source and eco-friendly cyanide source,
wide scope of substrates with good functional group
tolerance, and simple work-up procedure.
Keywords:
calcium
carbide;
potassium
hexacyanoferrate(II); one-pot procedure; four-component
synthesis; β-cyano-α,β-unsaturated ketone
Figure 1. Representative examples containing β-cyano-
α,β-unsaturated ketone moiety.
In the past years, a few synthetic methods for β-
cyano-α,β-unsaturated ketones were reported
(Scheme 1), which included i) the reactions of
(phenacylidene)triphenylphosphorane with benzoyl
cyanide;[8] ii) the palladium-catalyzed reactions of
arylacetylenes with aroyl cyanides;[9] iii) the nickel-
catalyzed conjugate addition of trimethylsilyl cyanide
to ynones;[10] and iv) the reactions of cyclic bromo
imidates with triethylamine.[11] However, there are a
number of problems with these synthetic methods,
such as environment-unfriendly reagents, limited
sources of raw materials, limited functional group
compatibility, lengthy synthetic steps and unsafe
cyanide sources, etc. Therefore, it is the focus of
research in this field to develop a more efficient,
green and practical method for the synthesis of β-
cyano-α,β-unsaturated ketones and to expand their
application range.
β-Cyano-α,β-unsaturated ketones contain important
functional groups, such as cyano, carbonyl and
alkenyl, which are significant intermediates for the
synthesis of fine chemicals, such as pharmaceuticals,
pesticides and perfumes.[1-3] At the same time, the
substances
containing
β-cyano-α,β-unsaturated
ketone moieties also have great potential application
value.[4] Figure 1 shows two structures which can
separately be used as a calciumchannel blocker
(treating hypertension, cerebral artery occlusion[5] and
Alzheimer’s disease[6]) and a new type of near-
infrared dye.[7]
1
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10.1002/adsc.201900733
Advanced Synthesis & Catalysis
conditions. The different ligands, catalysts, bases and
solvents were attempted to synthesize β-cyano-α,β-
unsaturated ketone. The results are shown in Table 1.
The reaction was first conducted in DMF using
Pd(OAc)2 as a catalyst, Cs2CO3 as a base in the
absence of a ligand. The product (Z)-4-oxo-2,4-
diphenylbut-2-enenitrile (3a) was obtained in 45%
yield (Table 1, entry 1). Only Z-type structure was
observed, which was determined by comparison with
10]
literature data.[9a,
The reaction yield could be
improved in the presence of some ligands such as
PPh3, dppe, dppp and dppb (entries 2−5). Among
them, dppb exhibited the best ligand effect (entry 5).
In addition, it was found that Pd(II) catalysts, such as
Pd(OAc)2, PdCl2 and Pd(PPh3)2Cl2, could catalyze the
reaction to give 3a in moderate to good yield (entries
5−7). Pd(OAc)2 as a catalyst could give best yield
(entry 5). However, Pd(0) complex, for example
Pd(PPh3)4, did not exhibit catalytic effect on the
reaction (entry 8). Bases played a prominent role in
the reaction. Some inorganic bases, such as Cs2CO3,
K2CO3, Na2CO3, KOAc and NaOH, exhibited
moderate to good activities for the reaction (entries 5,
9−12). In contrast, organic bases, such as Et3N, DBU,
DMAP and DABCO, could not give the desired
product (entries 13−16). The best yield for 3a was
obtained by using K2CO3 as a base (entry 9). Solvents
also had certain effect on the yield of 3a. Besides
DMF, the reaction in DMAc, DMSO, MeCN, PhMe
and 1,4-dioxane were also attempted (entries 17−21),
but no better yield for 3a was observed in comparison
with DMF (entry 9).
Scheme 1. Preparation of β-cyano-α,β-unsaturated
ketones
Calcium carbide, CaC2, is commercial available
solid, which is stable and inexpensive, and
extensively used as a raw material of acetylene gas by
hydrolysis in chemical industry. The recent reports
have revealed that calcium carbide can be directly
used as a sustainable, easy-to-handle, and low-cost
feedstock, and an efficient source of acetylene for in
situ chemical transformations.[12]
On the basis of the optimized reaction
conditions, the four-component reactions of
various aryl iodides with CaC2, K4[Fe(CN)6] and
aroyl chloride were used to synthesize β-cyano-
α,β-unsaturated ketones. The results are
summarized in Table 2. It was found that aryl
iodides containing electron-donating groups, such
as Me, n-Pr, n-Bu, n-pentyl and MeO, on
aromatic rings afforded the corresponding
products in good yield (3b−3g). Aryl iodides
containing electron-withdrawing groups, such as
F, Cl, Br, NO2 and CF3 on the ortho-, meta-, or
para-positions of phenyl group could also give
satisfactory yield (3h−3n). The reactions were
also suitable to different substituted aroyl
chlorides, and the corresponding products could
be obtained in moderate to good yield (3o−3z). In
addition, heteroaryl iodides, such as 2-
iodopyridine and 2-iodothiophene, could also be
suitable to this kind of reactions, and gave the
corresponding products in moderate to good yield
Potassium hexacyanoferrate(II), K4[Fe(CN)6], is a
byproduct of the coal chemical industry and
commercially available on a ton scale. It is also used
in the food industry for metal precipitation. In
addition, it has been described as an antiagglutinating
auxiliary for table salt (NaCl). Recently, K4[Fe(CN)6]
has been used as an eco-friendly cyanide source for
some organic reactions to synthesize important
compounds bearing cyano groups.[13]
Our recent research interests focused on the use of
CaC2 and K4[Fe(CN)6] in the organic synthesis,
respectively, and reported the synthesis of 2-
methylbenzofurans,[14]
triarylacrylonitriles[16]
diarylacetylenes,[15]
1,3,5-
and
triaroylcyclohexanes[17] direct using CaC2 as an
acetylene source, and the cyanation of unsaturated
compounds including C=O, C=N and/or C=C bonds
by nucleophilic addition reactions using K4[Fe(CN)6]
as an eco-friendly cyanide source.[18]
In this work, we report a more efficient and green
method for the combined use of two cheap and safe
inorganic chemicals, CaC2 as an easy-to-handle
acetylene source and K4[Fe(CN)6] as an eco-friendly
cyanide source, in one reaction to synthesize β-
cyano-α,β-unsaturated ketones by one-pot four-
component procedure using commercial available
aryl halides and aroyl chlorides as substrates.
(3α, 3β).
Initially, the reaction of iodobenzene (1a), CaC2,
K4[Fe(CN)6] with benzoyl chloride (2a) was selected
as a model reaction to optimize the reaction
2
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10.1002/adsc.201900733
Advanced Synthesis & Catalysis
Table 1． Optimization of the reaction conditionsa
Table 2. Synthesis of β-cyano-α,β-unsaturated ketones
from aryl iodidesa
Entry
Catalyst
Ligand
Base
Solvent
Yield
(%)b
45
1
2
Pd(OAc)2
Pd(OAc)2
-
Cs2CO3
Cs2CO3
DMF
DMF
PPh3
46
48
55
3
4
Pd(OAc)2
Pd(OAc)2
dppe
dppp
Cs2CO3
Cs2CO3
DMF
DMF
5
6
Pd(OAc)2
PdCl2
dppb
dppb
Cs2CO3
Cs2CO3
DMF
DMF
66
43
7
8
PdCl2(PPh3)2
Pd(PPh3)4
dppb
dppb
Cs2CO3
Cs2CO3
DMF
DMF
51
NR
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
K2CO3
Na2CO3
KOAc
NaOH
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
DMSO
72
57
10
11
12
13
14
15
16
17
18
32
39
NR
NR
NR
NR
66
DBU
DMAP
DABCO
K2CO3
K2CO3
a
33
Reaction condition: K4[Fe(CN)6] (0.1 mmol), aroyl
chloride (0.5 mmol) and Pd(OAc)2 (0.05 mmol) stirred
first at 150 °C for 4 h, then aryl iodide (0.5 mmol), CaC2
(1.25 mmol), H2O (2.50 mmol), K2CO3 (0.25 mmol) and
dppb (0.05 mmol) in 4 mL of degassed and dried DMF
were added under nitrogen atmosphere and stirred at
80 °C for 28 h.
19
20
21
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
dppb
dppb
dppb
K2CO3
K2CO3
K2CO3
MeCN
PhMe
NR
Trace
NR
1,4-Dioxane
In addition, various aryl bromides, instead of
aryl iodides, could also be used in four-
component synthesis under optimized reaction
conditions. The results are summarized in Table
3. Fifteen examples of β-cyano-α,β-unsaturated
ketones could be obtained in satisfactory yield.
However, the yield of the corresponding
products was slightly lower than that of aryl
iodides.
a
Reaction condition: K4[Fe(CN)6] (0.1 mmol), benzoyl
chloride (2a) (0.5 mmol) and catalyst (0.05 mmol) stirred
first at 150 °C for 4 h, then iodobenzene (1a) (0.5 mmol),
CaC2 (1.25 mmol), H2O (2.50 mmol), base (0.25 mmol)
and ligand (0.05 mmol) in 4 mL of degassed and dried
solvent were added under nitrogen atmosphere and stirred
at 80 °C for 28 h. bIsolated yield.
3
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10.1002/adsc.201900733
Advanced Synthesis & Catalysis
of iodobenzene, 1.60 g of CaC2, 0.74 g of K4[Fe(CN)6]
and 1.15 mL of benzoyl chloride in 50 mL of
degassed and dried DMF was performed to give 1.45
g of 3a in 62% isolated yield. The success of this
gram-reaction further demonstrated the effectiveness
of the optimized condition of the process (Scheme 3).
Table 3. Synthesis of β-cyano-α,β-unsaturated ketones
from aryl bromidesa
Scheme 3. Gram-scale synthesis of 3a.
Reaction
Conditions: K4[Fe(CN)6] (2 mmol), benzoyl chloride (10
mmol) and Pd(OAc)2 (1 mmol) stirred first at 150 °C for 4
h, then iodobenzene (10 mmol), CaC2 (25 mmol), H2O (50
mmol), K2CO3 (5 mmol) and dppb (1 mmol) in 50 mL of
degassed and dried DMF were added under nitrogen
atmosphere and stirred at 80 °C for 28 h.
In experimental process, it was observed that (Z)-
β-cyano-α,β-unsaturated ketones could partially
convert into (E)-β-cyano-α,β-unsaturated ketones at
room temperature. For example, 3a in CHCl3 placed
at room temperature for 24 h could transform into its
E isomer in 9% isolated yield. Similarly, 3l could
transform into its E isomer in 72% isolated yield
(Scheme 4).
a
Reaction condition: K4[Fe(CN)6] (0.1 mmol), aroyl
chloride (0.5 mmol) and Pd(OAc)2 (0.05 mmol) stirred
first at 150 °C for 4 h, then aryl bromide (0.5 mmol),
CaC2 (1.25 mmol), H2O (2.50 mmol), K2CO3 (0.25
mmol) and dppb (0.05 mmol) in 4 mL of degassed and
dried DMF were added under nitrogen atmosphere and
stirred at 80 °C for 28 h.
It is noteworthy to mention that reaction substrates
and reagents could also be extended. When Fe(III)
complex, K3[Fe(CN)6], was used to replace Fe(II)
complex, K4[Fe(CN)6], in the reaction, the product 3a
could also be obtained in 35% yield (Scheme 2).
Scheme 4. Transformation of Z-type to E-type of β-cyano-
α,β-unsaturated
ketones. Conditions: β-cyano-α,β-
unsaturated ketones in CHCl3 (2 mL) placed at room
temperature for 24 h.
In order to investigate the reaction mechanism,
several control experiments were carried out (Scheme
5). i) The two-component mixture of benzoyl
o
chloride (2a) with K4[Fe(CN)6] was heated at 150 C
to give benzoyl cyanide as a product in 91% yield.
This indicated that benzoyl cyanide possibly is an
intermediate of the four-component reaction. No
reaction was observed at 80 oC; ii) The two-
component reaction of 0.5 mmol of iodobenzene (1a)
with 1.25 mmol of calcium carbide catalyzed by
Pd(OAc)2 afforded phenylacetylene in 79% yield.
This result implied that phenylacetylene possibly is
also an intermediate of four-component reaction; iii)
The reaction of the resulting benzoyl cyanide and
phenylacetylene under the standard condition
produced β-cyano-α,β-unsaturated ketone 3a in 66%
yield. This result further demonstrated that both
benzoyl cyanide and phenylacetylene might be the
intermediates of the four-component reaction.
Scheme 2. Synthesis of 3a using K3[Fe(CN)6] instead
of K4[Fe(CN)6]. Reaction condition: K3[Fe(CN)6] (0.1
mmol), 2a (0.5 mmol) and Pd(OAc)2 (0.05 mmol) stirred
first at 150 °C for 8 h, then 1a (0.5 mmol), CaC2 (1.25
mmol), H2O (2.50 mmol), K2CO3 (0.25 mmol) and dppb
(0.05 mmol) in 4 mL of degassed and dried DMF were
added under nitrogen atmosphere and stirred at 80 °C for
28 h.
With the ubiquitous success of this protocol, the
synthesis of 3a by four-component reaction of
iodobenzene, CaC2, K4[Fe(CN)6] and benzoyl
chloride could also be carried out on a gram scale.
Under optimized conditions, the reaction of 1.12 mL
4
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10.1002/adsc.201900733
Advanced Synthesis & Catalysis
potassium hexacyanoferrate(II) as an eco-friendly
cyanide source, good substrate scope for aryl halides
and aroyl chlorides, inexpensive and commercial
available raw materials, high functional tolerance,
satisfactory yield and simple work-up procedure. A
gram-scale reaction further demonstrates the efficacy
of this synthetic method. This will be a good
alternative to the synthesis of wide range of β-cyano-
α,β-unsaturated ketones.
Scheme 5. Control experiments
Based on the above control experiments, a
plausible mechanism is proposed for the four-
component synthesis of β-cyano-α,β-unsaturated
ketones (Scheme 6). Oxidative addition of aryl
iodide (ArI) to a palladium(0) species, PdL2, which is
generated most commonly from palladium diacetate
and dppb,[19] forms an arylpalladium iodide complex
A. Complex A reacts with acetylene calcium
hydroxide B, which formed in situ by the reaction of
calcium carbide with water,[12f,12g] in the presence of
potassium carbonate to obtain palladium complex C.
Complex C undergoes reductive elimination to obtain
arylacetylene calcium hydroxide D. D hydrolyzes in
the presence of water to give arylacetylene E. At the
same time, potassium hexacyanoferrate(II) reacts
Experimental Section
General procedure: The mixture of K4[Fe(CN)6] (0.1
mmol), aroyl chlorides (0.5 mmol) and Pd(OAc)2 (0.05
mmol) was first stirred at 150 °C for 4 h, then aryl halides
(0.5 mmol), CaC2 (1.25 mmol), H2O (2.50 mmol), K2CO3
(0.25 mmol) and dppb (0.05 mmol) in 4 mL of degassed
and dried DMF were added under nitrogen atmosphere and
stirred at 80 °C for 28 h. The reaction was monitored by
TLC. After the completion, the resulting mixture was
filtered to remove the solid, and the liquor was extracted
with ethyl acetate (3×10 mL), and washed with saturated
brine (3×10 mL). The resulting organic phase was dried
with anhydrous sodium sulfate, and concentrated under
reduced pressure. The residue was isolated by column
chromatography using petroleum ether and ethyl acetate
(v/v 7:1) as eluent to give pure (Z)-4-oxo-2,4-diarylbut-2-
enenitriles 3a−z and 3α−β.
with aroyl chlorides to give aroyl cyanide F.[18b]
F
further reacts with PdL2 through oxidative addition to
form aroyl palladium cyanide G.[9a] The addition of G
to E gives vinyl palladium intermediate H.[9a]
H
undergoes reductive elimination to give the final
product, β-cyano-α,β-unsaturated ketone.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (21462038) for the financial support of this work.
Conflict of Interest
The authors declare no conflict of interest.
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Scheme 6. Proposed mechanism for four-component
synthesis of β-cyano-α,β-unsaturated ketones
In conclusion, a palladium-catalyzed one-pot four-
component synthetic method for β-cyano-α,β-
unsaturated ketones has developed. The salient
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carbide as an easy-to-handle acetylene source,
5
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10.1002/adsc.201900733
Advanced Synthesis & Catalysis
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This article is protected by copyright. All rights reserved.

10.1002/adsc.201900733
Advanced Synthesis & Catalysis
Palladium-Catalyzed One-Pot Four-Component Synthesis of β-
Cyano-α,β-unsaturated Ketones Using Calcium Carbide as an
Acetylene Source, Potassium Hexacyanoferrate(II) as an Eco-
Friendly Cyanide Source
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900733
Advanced Synthesis & Catalysis
Palladium-Catalyzed
One-Pot
Four-Component
Synthesis of β-Cyano-α,β-unsaturated Ketones Using
Calcium Carbide as an Acetylene Source, Potassium
Hexacyanoferrate(II) as an Eco-Friendly Cyanide Source
Adv. Synth. Catal. Year, Volume, Page–Page
Hao Lu, Zheng Li*
8
This article is protected by copyright. All rights reserved.