Palladium-Catalyzed Oxidative Carbonylative Coupling of Arylallenes, Arylboronic Acids, and Nitroarenes

Article abstract of DOI:10.1021/acs.orglett.9b02925

In this Letter, a palladium-catalyzed multicomponent procedure for the selective synthesis of α-substituted α,β-unsaturated ketones has been developed. With readily available allenes, arylboronic acids, and nitroarenes as the substrates, the reaction proceeds selectively to the desired α-substituted enones. Notably, no manipulation of carbon monoxide gas is needed here, and Mo(CO)₆ has been applied as a stable solid CO source instead. Additionally, as an oxidative coupling reaction, nitroarenes are used as both the amine source and the oxidant to regenerate the active palladium species.

Full text of DOI:10.1021/acs.orglett.9b02925

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Oxidative Carbonylative Coupling of
Arylallenes, Arylboronic Acids, and Nitroarenes
Hui-Qing Geng,† Jin-Bao Peng,† and Xiao-Feng Wu*,†,‡
†Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of China
‡Leibniz-Institut fu
̈
r Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Straβe 29a, 18059 Rostock, Germany
̈
S
* Supporting Information
ABSTRACT: In this Letter, a palladium-catalyzed multicomponent procedure for the selective synthesis of α-substituted α,β-
unsaturated ketones has been developed. With readily available allenes, arylboronic acids, and nitroarenes as the substrates, the
reaction proceeds selectively to the desired α-substituted enones. Notably, no manipulation of carbon monoxide gas is needed
here, and Mo(CO)6 has been applied as a stable solid CO source instead. Additionally, as an oxidative coupling reaction,
nitroarenes are used as both the amine source and the oxidant to regenerate the active palladium species.
n modern organic synthesis, in particular, under the
background of sustainable development and green chem-
become interested in developing a carbonylation procedure for
allene transformation with nitroarenes as the amine source and
oxidant.
I
istry, the request for high reaction efficiency has reached a new
level.1 One aspect of reaction efficiency is the number of newly
formed chemical bonds in one reaction: the new chemical
bond formation efficiency. Among the various options, the
multicomponent reaction offers an ideal choice.2 However,
when combining multiple reactive reagents, it is a great
challenge to find a balance between the reactivity and the
selectivity.3 This task has been taken on by chemists in the past
decades, and many novel multicomponent procedures have
been established.1,2,4
On the contrary, palladium-catalyzed carbonylative trans-
formations have experienced great progress since their first
report in the 1970s.5 Numerous carbonyl-containing com-
pounds can be easily prepared by carbonylation procedures. In
these procedures, the acylpalladium complex is the common
key intermediate, which is highly reactive and nonstable.
Hence it is even more labyrinthine with the presence of an
acylpalladium complex in the multicomponent reactions.6
Concerning the substrates applicable, the reaction complexity
will increase even more when using allene as one of the starting
materials. Allenes are useful materials in synthetic chemistry
due to the exceptional reactivity of the 1,2-diene moiety. They
allow the rapid construction of complexed molecules.7 As
expected, various novel carbonylative transformations of
allenes have been explored as well, which are mainly three-
component reactions (including carbon monoxide).8,9 Addi-
tionally, anilines are commonly applied nucleophiles in
carbonylation chemistry and are produced from the corre-
sponding nitroarenes. Here nitroarenes have three traits: (1)
stable and abundant, (2) can be reduced by CO, and (3) can
be used as an oxidant for catalyst regeneration. Hence we have
Initially, we chose commercially available phenylallene,
phenylboronic acid, and 1-methyl-4-nitrobenzene as the
model substrates to establish the catalyst system. Notably,
from a theory point of view, at least 18 different kinds of
products are possible. (For a full list, see the Supporting
Information.) Indeed, when the reaction was tested with
Pd(TFA)2 as the catalyst and Na2CO3 as the base in MeCN at
100 °C, a real mixture of many nonidentifiable compounds was
obtained. To our delight, we were finally able to confirm that
8% of (Z)-1,3-diphenyl-2-((p-tolylamino)methyl)prop-2-en-1-
one (P1) was formed in our first testing (Table 1, entry 1).
With these encouraging results in hand, various inorganic bases
were subsequently tested (Table 1, entries 2−8). The obtained
yields varied with bases, and a 52% yield of the target product
was formed with KHCO3 as the base (Table 1, entry 8). Only a
16% yield was obtained when NEt3 or DiPEA (N,N-
diisopropylethylamine) was used as the base (Table 1, entries
9 and 10). The yield decreased when using a lower loading
base (Table 1, entry 11). Subsequently, several palladium
precursors were tested (Table 1, entries 12−16). The target
product was isolated in 55% yield with [Pd(cinnamyl)Cl]2 as
the catalyst (Table 1, entry 16). Additional efforts were made
to vary the other reaction parameters as well, such as the
reaction temperature, the ratio of reagents, the catalyst loading,
the water amount, and so on; however, no further improve-
ment of the yield could be realized.
Received: August 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02925
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Synthesis of α-Substituted Enones from
Arylboronic Acids
a
entry
palladium
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(OAc)2
PdCl2
Pd(MeCN)2Cl2
Pd2dba3
[Pd(cinnamyl)Cl]2
[Pd(cinnamyl)Cl]2
[Pd(cinnamyl)Cl]2
base
yield
1
2
3
4
5
6
7
8
Na2CO3
Cs2CO3
K2CO3
NaHCO3
K3PO4
K2HPO4
KH2PO4
KHCO3
NEt3
8
9
28
20
34
40
0
52
16
16
9
10
11
12
13
14
15
16
17
18
DiPEA
b
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
29
22
43
44
c
37
c
55
d
24
22
e
a
Reaction conditions: phenylboronic acid (0.5 mmol), phenylallene
(1.2 equiv), 1-methyl-4-nitrobenzene (3 equiv), Pd(TFA)2 (5 mol
%), DPPP (5 mol %), Mo(CO)6 (1 equiv), base (2 equiv), H2O (5
equiv), CH3CN (2 mL), 100 °C, 14 h, yields determined by 1H NMR
analysis using 1,3,5-trimethoxybenzene as an internal standard.
a
Reaction conditions: arylboronic acid (0.5 mmol), phenylallene (1.2
equiv), 1-methyl-4-nitrobenzene (3 equiv), [Pd(cinnamy)Cl]2 (2.5
mol %), DPPP (5 mol %), Mo(CO)6 (1 equiv), KHCO3 (2 equiv),
H2O (5 equiv), CH3CN (2 mL), 100 °C, 14 h, isolated yields.
b
c
d
KHCO3 (1 equiv). 2.5 mol %, isolated yield. [Pd(cinnamyl)-
e
Cl]2(2.5 mol %), 1-methyl-4-nitrobenzene (2 equiv). [Pd(cinnamyl)-
Cl]2(2.5 mol %), 1-methyl-4-nitrobenzene (10 equiv).
in our control experiments as well. (See the Supporting
Information.) In more detail, no desired product could be
detected by using p-toluidine instead of 1-methyl-4-nitro-
benzene, and a mixture of two products was obtained when a
combination of p-toluidine (1 equiv) and nitrobenzene (2
equiv) was used under standard conditions. However, no
desired product could be detected when nitroalkanes were
tested, such as nitromethane and nitroethane.
Finally, the generality of the applicable allenes was checked
as well (Scheme 3). Various arylallenes were prepared and
reacted under our conditions; good yields of the corresponding
enones were produced. In particular, the chloride-decorated
products were ready for further transformations via cross-
coupling reactions.10 It is also worth mentioning that aliphatic
allenes were prepared and tested as well, but no desired
product could be detected.
With the best reaction conditions in hand, we tested the
effects of arylboronic acids (Scheme 1). As we expected, the
yields were increased when arylboronic acid was substituted
with electron-donating groups (Scheme 1, P2−P9). In the case
of using 4-methoxyphenylboronic acid as one of the starting
materials, 83% of the target molecular can be isolated (Scheme
1, P7). Because of the steric effect, the yield of the target
product decreased when arylboronic acid contained an ortho
substitution (Scheme 1, P4). This type of steric effect can be
decreased if the substitution is substituted at the meta or the
better para position (Scheme 1, P3, P8). Besides fluoro- and
chloro-substituted arylboronic acids, thiophen-3-ylboronic acid
can be applied as the substrate as well, and moderate yields of
the corresponding products can be isolated in all cases
(Scheme 1, P11−P15).
Then, we keep 4-methoxyphenylboronic acid and phenyl-
allene as the standard substrates, and various nitroarenes were
tested under our typical reaction conditions (Scheme 2).
Moderate to excellent yields can be obtained, in general. From
the obtained results, the position of the substitution in
nitroarene has shown a low effect on the reaction outcome.
Both electron-donating and electron-withdrawing functional
groups can be well tolerated. Notably, thioether and terminal
alkene can also be tolerated and gave the corresponding
products in 72 and 54% isolated yield, respectively (Scheme 2,
P20 and P22). These two functional groups are easily oxidized
in the presence of the standard oxidant, which also proves the
advantage of using nitroarene as the oxidant. It is important to
mention that we have proven nitroarene to act in the oxidation
On the basis of our results and literature,8,9 a possible
reaction mechanism is proposed as well (Scheme 4). The
reaction started with a base-promoted transmetalation of
arylboronic acid with the active palladium(II) complex to give
the corresponding aryl−Pd(II) intermediate. Then, carbon
monoxide inserted into the C−Pd bond via coordination with
free CO or ligand exchange with Mo(CO)6 to give the acyl−
palladium complex as the key intermediate. Subsequently, the
active acyl−palladium complex reacted with the internal
carbon (which is more reactive) of allene, followed by the
nucleophilic attack of aniline to give the final enone products.
Meanwhile, the active palladium complex was regenerated for
the next catalytic cycle.
In summary, a palladium-catalyzed multicomponent proce-
dure for the selective synthesis of α-substituted α,β-
B
DOI: 10.1021/acs.orglett.9b02925
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of α-Substituted Enones from
Nitroarenes
Scheme 4. Proposed Reaction Mechanism
a
unsaturated ketones has been developed. With readily available
allenes, arylboronic acids, and nitroarenes as the substrates, the
reaction proceeds selectively to the desired α-substituted
enones in moderate to excellent yield. Notably, no
manipulation of carbon monoxide gas is needed here, and
Mo(CO)6 has been applied as a stable solid CO source
instead. Additionally, as an oxidative coupling reaction,
nitroarenes are used as both the amine source and the oxidant
to regenerate the active palladium species
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Reaction conditions: 4-Methoxyphenylboronic acid (0.5 mmol),
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02925.
phenylallene (1.2 equiv), nitroarene (3 equiv), [Pd(cinnamy)Cl]2
(2.5 mol %), DPPP (5 mol %), Mo(CO)6 (1 equiv), KHCO3 (2
equiv), H2O (5 equiv), CH3CN (2 mL), 100 °C, 14 h, isolated yields.
General comments, general procedure, optimization
details, analytic data and NMR spectra (PDF)
a
Scheme 3. Synthesis of α-Substituted Enones from Allenes
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiao-feng.wu@catalysis.de.
ORCID
Xiao-Feng Wu: 0000-0001-6622-3328
Funding
We acknowledge the financial support from the National
Natural Science Foundation of China (21772177, 21801225).
Notes
The authors declare no competing financial interest.
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Org. Lett. XXXX, XXX, XXX−XXX