Palladium-Catalyzed Carbonylative Synthesis of α,β-Unsaturated Amides from Styrenes and Nitroarenes

Article abstract of DOI:10.1021/acs.orglett.8b02109

A procedure on palladium-catalyzed selective aminocarbonylation of styrenes with nitroarenes for the synthesis of α,β-unsaturated amides has been developed. A range of substituted α,β-unsaturated amides were synthesized in moderate to good yields. Interestingly, nitroarenes act as both a nitrogen source and oxidant, and Mo(CO)₆ acts as a solid CO source and reductant in this catalytic system.

Full text of DOI:10.1021/acs.orglett.8b02109

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Carbonylative Synthesis of α,β-Unsaturated
Amides from Styrenes and Nitroarenes
Jin-Bao Peng,*,† Hui-Qing Geng,† Da Li,† Xinxin Qi,† Jun Ying,† and Xiao-Feng Wu*,†,‡
†Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, People’s Republic of China
‡Leibniz-Institut fu
̈
r Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Straße 29a, Rostock 18059, Germany
̈
S
* Supporting Information
ABSTRACT: A procedure on palladium-catalyzed selective aminocarbonylation of styrenes with nitroarenes for the synthesis
of α,β-unsaturated amides has been developed. A range of substituted α,β-unsaturated amides were synthesized in moderate to
good yields. Interestingly, nitroarenes act as both a nitrogen source and oxidant, and Mo(CO)6 acts as a solid CO source and
reductant in this catalytic system.
unsaturated amides.5 This process can be promoted by a
α,β-Unsaturated amides are an important structural motif that
tributyltin radical as well and proceeds via a radical/polar
crossover process (Scheme 1, eq b).5c In addition, Beller, Lei
and their co-workers developed a Pd/Cu-catalyzed aerobic
oxidative N-dealkylative carbonylation procedure for α,β-
unsaturated amide synthesis. The reaction started from tertiary
amines and alkenes under a CO/O2 mixed gas atmosphere
(Scheme 1, eq c).6a Despite their great reaction efficiency,
these procedures usually require the usage of pressurized CO
gas which limited their applications in synthetic laboratories
and also increased manipulation costs. Indeed, although a
transition-metal-catalyzed carbonylation reaction has experi-
enced tremendous development and applications,7 synthetic
chemists are continuously exploring CO surrogates.8
On the other hand, compared with aniline derivatives,
nitroarenes are an attractive nitrogen source due to their low
cost and wide availability. Nitro compounds have been used in
a series of reductive amination reactions and many other
transformations.9 However, only a few examples have been
reported using nitroarenes in aminocarbonylation reactions.10
Beller and co-workers reported their achievements on
palladium-catalyzed aminocarbonylation of olefins with nitro-
arenes to give aliphatic amides in good yields.10a Driver and
colleagues developed a palladium-catalyzed aminocarbonyla-
tion procedure for producing aromatic amides from arenes and
nitroarenes via C−H bond activation.10b
is present in a wide range of natural products, pharmaceuticals,
and polymeric materials.1 Additionally, α,β-unsaturated amides
also serve as versatile building blocks in organic synthesis.2
They are not only viable for further functionalization but also
active for reactions such as nucleophilic addition and pericyclic
reactions. Due to their important applications in pharmaceut-
icals and synthetic chemistry, the development of new and
efficient synthetic methods for their preparation has attracted
continuous interest from organic chemists in recent years.3
Traditional methods are based on nucleophilic substitution of
carboxylic acid derivatives with amines in the presence of
activating reagents (Scheme 1, eq a).4 Alternatively, transition-
metal-catalyzed hydroaminocarbonylation of alkynes with
primary and secondary amines provides an efficient and
atom-economic method for the synthesis of N-substituted α,β-
Scheme 1. Synthesis of α,β-Unsaturated Amides
Recently, Hu and co-workers developed a nickel-catalyzed
reductive aminocarbonylation method for transforming aryl
halides and nitroarenes into the corresponding aromatic
amides.10c However, there is no report on the amino-
carbonylation of alkenes with nitroarenes for the synthesis of
Received: July 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02109
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
α,β-unsaturated amides. Under the aforementioned conditions,
and with our continued interest in developing new CO gas-free
carbonylation reactions,11 we herein report a palladium-
catalyzed aminocarbonylation of alkenes with nitroarenes for
the synthesis of α,β-unsaturated amides employing Mo(CO)6
as the solid CO source (Scheme 1, eq d).
Initially, styrene 1a and 4-nitrotoluene 2d were selected as
the model substrates for establishing this aminocarbonylation
system. As the first step, a series of commercially available
phosphine ligands were examined with Pd(acac)2 as the
catalyst and p-toluenesulfonic acid was used as the additive in
1,4-dioxane in the presence of Mo(CO)6. When monodentate
phosphine ligands such as PPh3 and PCy3 were used, no
desired α,β-unsaturated amide product 3ad could be observed
(Table 1, entries 1 and 2; see details in Supporting Information
improved to 27% at 130 °C, but further increasing the reaction
temperature resulted in a decreased yield (Table 1, entries 7
and 8). This observation is explainable since a high reaction
temperature would facilitate the release of CO from Mo(CO)6,
while a high reaction temperature would result in the
dissociation of the palladium carbonyl complex. Increasing
the catalyst loading to 5 mol % improved the yield significantly,
and the desired product 3ad was obtained in 56% yield (Table
1, entry 9). Subsequently, a series of acid additives were
evaluated, and comparable yields were obtained when
benzenesulfonic acid derivatives were used as an additive
(Table 1, entries 10−12). The best result was obtained when
20 mol % of benzenesulfonic acid monohydrate was used, and
the reaction afforded 3ad in 59% yield (Table 1, entry 12). No
amonicarbonylation reaction occurred in the absence of an
acid additive (Table 1, entry 13). Further sceening of other
reaction parameters such as solvent and the amount of
Mo(CO)6 did not improve the reaction yield (Table 1, entry
14). Finally, the concentration of the reactant affected the yield
significantly; a higher yield of 3ad was obtained when the
reaction was performed at a higher concentration (Table 1,
entry 15). It should be mentioned that the stereo- and
regioselectivity of this aminocarbonylation reaction turned out
to be excellent; the linear E-α,β-unsaturated amide was
obtained as the sole isomer.
With the optimized conditions in hand (Table 1, entry 15),
we investigated the substrate scope of this aminocarbonylation
reaction with respect to nitroarenes. As summarized in Figure
1, a series of different nitroarenes were successfully applied
under the standard reaction conditions and the corresponding
α,β-unsaturated amides were produced in moderate to good
yields. Nitrobenzene 2a reacted with styrene 1a and produced
N-phenylcinnamamide 3aa in 60% yield. Nitrobenzenes with
alkyl substitution at different positions of the benzene ring
were well tolerated and delivered the corresponding
cinnamamides in good yields (3ab−3ae). Ether substituents
were also compatible in this aminocarbonylation reaction and
produced the corresponding products in moderate to good
yields without breaking the C−O bonds (3af−3ah). The
electronic properties of the substituents affected the reaction
yields significantly. Substrates with electron-donating groups
give higher yields than those with electron-withdrawing groups.
When nitrobenzenes with halides such as fluoro- and chloro-
substituents were used in this reaction, only moderate yields
were obtained (3ai−3an).
Table 1. α,β-Unsaturated Amides Synthesis: Optimization
a
of the Reaction Conditions
b
entry
[Pd]
ligand
additive
temp (°C) yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(TFA)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
PPh3
PCy3
PTSA·H2O
PTSA·H2O
PTSA·H2O
PTSA·H2O
PTSA·H2O
PTSA·H2O
PTSA·H2O
PTSA·H2O
PTSA·H2O
4-Cl-BSA
PPTS
120
120
120
120
120
110
130
140
130
130
130
130
130
130
130
0
0
15
trace
9
trace
27
15
56
46
53
59
0
DPPP
DPPB
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
c
c
c
c
BSA·H2O
−
BSA·H2O
c
13
14
15
cd
,
60
89
ce
,
BSA·H2O
a
Reaction conditions: styrene (0.5 mmol), 4-nitrotoluene (1.5
mmol), [Pd] (2 mol %), ligand (6 mol % for monodentate ligand,
3 mol % for bidentate ligand), Mo(CO)6 (1.0 mmol), additive (20
b
mol %), 1,4-dioxane (2 mL), 14 h. Yields were determined by GC
c
using dodecane as an internal standard. Pd(acac)2 (5 mol %), DPPP
d
e
(7.5 mol %). Mo(CO)6 (2.0 mmol). 1,4-Dioxane (0.5 mL). DPPP:
1,3-bis(diphenylphosphino)propane. DPPB: 1,4-bis(diphenyl-
phosphino)butane. PTSA·H2O: p-toluenesulfonic acid monohydrate.
4-Cl-BSA: 4-chlorobenzenesulfonic acid. PPTS: pyridinium p-toluene-
sulfonate. BSA·H2O: benzenesulfonic acid monohydrate.
Subsequently, we turned our attention to examine the
generality of the alkene coupling partner for this amino-
carbonylation reaction. As illustrated in Figure 2, a range of
aryl substituted olefins were well tolerated in this reaction.
Both electron-donating group (3bd−3gd) and electron-
withdrawing group (3hd−3kd) substituted styrene derivatives
were well tolerated and produced the desired products in
moderate to good yields. In addition, 2-vinylnaphthalene 1l
reacted with 4-nitrotoluene 2d smoothly and the correspond-
ing α,β-unsaturated amide 3ld was isolated in 76% yield.
However, when an alkyl substituted olefin such as oct-1-ene
was used in this reaction, a mixture of unseparatable isomers
with the migration of double bond was observed.12 It is also
important to mention that when trans-β-methylstyrene, α-
methylstyrene, or allylbenzene was tested with 4-nitrotoluene
under our standard reaction conditions, no desired product
could be detected.
(SI)). To our delight, when 1,3-bis(diphenylphosphino)-
propane (DPPP) was used as the ligand, the amino-
carbonylation reaction proceeded successfully and gave the
desired N-(p-tolyl)cinnamamide 3ad in 15% yield (Table 1,
entry 3). However, other bidentate phosphine ligands
including DPPB were inefficient for this transformation;
none or only a trace amount of the desired product could be
detected (Table 1, entry 4; see details in SI). Next, different
palladium catalyst precursors were investigated, and the yield
of the desired product decreased to 9% when Pd(TFA)2 was
used as the catalyst (Table 1, entry 5). The reaction
temperature played an important role in this reaction; only a
trace amount of 3ad was observed when the reaction was
performed at 110 °C (Table 1, entry 6). The yield was slightly
B
DOI: 10.1021/acs.orglett.8b02109
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In order to gain a better understanding of the reaction
pathway of this aminocarbonylation reaction, control experi-
ments were conducted (Scheme 2). When p-toluidine 4d was
Scheme 2. Mechanistic Studies
treated with styrene 1a under the standard reaction conditions,
no cinnamamide 3ad could be detected. Only a trace amount
of N-formylation product of 4d was observed (Scheme 2, eq
a). However, when a mixture of 4-nitrotoluene 2d and aniline
4a was reacted with styrene 1a under the standard conditions,
α,β-unsaturated amides 3ad and 3aa were obtained in 31% and
33% yields, respectively (Scheme 2, eq b). These observations
indicate that the presence of nitroarene is critical for this
reaction, and the nitroarene acts as both a nitrogen source and
an oxidant here. Mo(CO)6 acts as both a CO source and
reductant in this catalytic system as well. As the reaction
between nitroarene and CO can in situ produce isocyanate as
well, p-tolyl isocyanate 5d was subjected and no desired
product 3ad could be observed (Scheme 2, eq c). This control
reaction excluded the possibility of isocyanate as an
intermediate in this transformation. Nitrosobenzene was tested
under our standard conditions as well; however, only aniline as
the reduced product could be detected.
Figure 1. α,β-Unsaturated amides synthesis: substrates scope of
nitroarenes. Reaction conditions: styrene (0.5 mmol), nitroarenes
(3.0 equiv), Pd(acac)2 (5 mol %), DPPP (7.5 mol %), Mo(CO)6 (1.0
mmol), benzenesulfonic acid monohydrate (20 mol %), 1,4-dioxane
(0.5 mL), 130 °C, 14 h, isolated yields.
Although the detailed reaction mechanism of this reaction is
unclear at this stage, a plausible mechanism for this
aminocarbonylation reaction is proposed and shown in
Scheme 3 based on our preliminary observations and the
previous literature. Initially, nitrobenzene 2 was reacted with
Scheme 3. Plausible Mechanism
Figure 2. α,β-Unsaturated amides synthesis: substrates scope of
styrenes. Reaction conditions: alkene (0.5 mmol), 4-nitrotoluene (3.0
equiv), Pd(acac)2 (5 mol %), DPPP (7.5 mol %), Mo(CO)6 (1.0
mmol), benzenesulfonic acid monohydrate (20 mol %), 1,4-dioxane
(0.5 mL), 130 °C, 14 h, isolated yields.
C
DOI: 10.1021/acs.orglett.8b02109
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Organic Letters
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Pd(II), which generated in situ from a palladium precursor and
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elimination, the desired α,β-unsaturated amide product 3 will
be eliminated and the released Pd(0) species will be reoxidized
back to the active Pd(II) complex 10 for the next catalytic
cycle.
In summary, we have developed a palladium-catalyzed
stereo- and regioselective aminocarbonylation of alkenes with
nitroarenes for the synthesis of α,β-unsaturated amides. A
range of substituted α,β-unsaturated amides were prepared in
moderate to good yields. Mo(CO)6 was used as a solid CO
source and reductant. The reaction proceeded in a partially
redox-neutral manner where nitroarene acted as not only a
cheap and abundant nitrogen source but also an oxidant for the
generation of Pd(II) catalyst.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02109.
General comments, general procedures, analytic data,
and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pengjb_05@zstu.edu.cn.
*E-mail: xiao-feng.wu@catalysis.de.
ORCID
́
́
́
(3) (a) Concellon, J. M.; Perez-Andres, J. A.; Rodríguez-Solla, H.
Synthesis of (E)-α,β-unsaturated esters and amides with total
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2773−2275. (b) Feuillet, F. J. P.; Cheeseman, M.; Mahon, M. F.; Bull,
S. D. Stereoselective synthesis of (E)-trisubstituted α,β-unsaturated
amides and acids. Org. Biomol. Chem. 2005, 3, 2976−2989.
Xiao-Feng Wu: 0000-0001-6622-3328
Notes
The authors declare no competing financial interest.
́
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ACKNOWLEDGMENTS
■
The authors thank the NSFC (21472174, 21602201,
21602204, 21772177) and the Zhejiang Natural Science
Fund for Distinguished Young Scholars (LR16B020002) for
financial support.
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