Palladium-catalyzed highly regioselective hydroaminocarbonylation of aromatic alkenes to branched amides

Article abstract of DOI:10.1039/C7OB00371D

Pd(t-Bu₃P)₂ has been successfully identified as an efficient catalyst for the hydroaminocarbonylation of aromatic alkenes to branched amides under relatively mild reaction conditions. With hydroxylamine hydrochloride as an additive,

Full text of DOI:10.1039/C7OB00371D

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Palladium-catalyzed highly regioselective
hydroaminocarbonylation of aromatic alkenes to
Cite this: DOI: 10.1039/c7ob00371d
branched amides†
Received 15th February 2017,
Accepted 13th March 2017
a,b
Jinping Zhu,a Bao Gaob and Hanmin Huang
*
DOI: 10.1039/c7ob00371d
rsc.li/obc
Pd(t-Bu3P)2 has been successfully identified as an efficient catalyst established.6,7 Among possible approaches for the construc-
for the hydroaminocarbonylation of aromatic alkenes to branched tion of amides, the catalytic hydroaminocarbonylation of
amides under relatively mild reaction conditions. With hydroxyl- alkenes with amines in the presence of CO is, in principle, one
amine hydrochloride as an additive, both aliphatic and aromatic of the most straightforward and atom-efficient methods.
amines could be used as coupling partners for the present reac- Extensive studies on the hydroaminocarbonylation of alkenes
tion, leading to production of branched amides in high yields with have already been reported,8 but mostly focused on the use of
excellent regioselectivities.
aromatic amines as coupling partners. Furthermore, the for-
mation of branched amides from Pd-catalyzed hydroamino-
carbonylation is more challenging. This is often attributed to the
reluctance of the formation of the more sterically hindered sec-
ondary alkylpalladium species and the tendency of aliphatic
amines with strong basicity to retard the generation of the
active palladium hydride species, which is crucial for the cata-
lysis. To circumvent this problem, we have successfully devel-
oped a ternary catalyst system composed of Pd/acid/paraformal-
dehyde, which could enable aliphatic amines to be utilized as
coupling partners, leading to the formation of linear amides.9a
Further work from our group has demonstrated that a stoichio-
metric amount of hydroxylamine hydrochloride could promote
the desired palladium-catalyzed hydroaminocarbonylation
with aliphatic amines to proceed well.9b Recently, Beller and
coworkers developed a strategy to utilize amine hydrochlorides
as amine sources under the catalysis of Pd/monophosphine.10
With monophosphine-ligated palladium as the catalyst, the
above catalytic protocol favored the formation of branched
amides at higher pressure (40 atm). More recently, we developed
an intramolecular hydroaminocarbonylation reaction with ali-
phatic amines and for the first time proved that the reaction
was indeed initiated by a palladium hydride species.11 We also
found that the reaction of alkenes with HPd(t-Bu3P)Cl favored
the formation of secondary alkylpalladium species, leading to
the formation of branched amides (Scheme 2, eqn (1)). Inspired
by these results, we envisioned that the catalytic hydroamino-
carbonylation of alkenes to branched amides would be realized
by using Pd(t-Bu3P)2 as a catalyst with the assistance of an acid.
Herein, we report the development of an efficient palladium
catalytic system for the hydroaminocarbonylation of aromatic
alkenes with both free aliphatic amines and aromatic amines
giving branched amides (Scheme 2, eqn (2)).
Amides have long been recognized as a valuable fundamental
structural motif in a variety of pharmacologically active com-
pounds, agrochemicals and synthetic organic materials.1
Branched amides, such as napropamide,2 carbetamide,3
naproanilide4 and flutamide,5 are a particularly important sub-
class of amides that often exhibit useful biological activities and
are widely represented in marketed drugs and bioactive com-
pounds (Scheme 1). The rapid synthesis of this structural motif
is thus of utmost importance to the drug discovery process.
Over the past few decades, many approaches to construct
amides from a variety of simple starting materials have been
Scheme 1 Pesticides and pharmaceuticals with branched amides.
aCollege of Chemical Engineering, Zhejiang University of Technology, Hangzhou,
310024, China. E-mail: hanmin@ustc.edu.cn
bDepartment of Chemistry, University of Science and Technology of China, Hefei,
230026, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c7ob00371d
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anisole is the best solvent and the reaction conducted at
120 °C could give the desired product in the highest yield with
excellent regioselectivity (see the ESI†). The acidic additive was
revealed to impact the reactivity significantly. When other
acidic amine hydrochlorides with different amine-moieties
were used instead of hydroxylamine hydrochloride as the co-
catalyst, only moderate yields were achieved (55% and 43%
yield, respectively; Table 1, entries 7 and 8). Nevertheless,
when other organic acids, such as PhCO2H, CH3CO2H, and
TsOH, served as additives, only a trace amount of amide was
detected (Table 1, entries 9–11). Finally, a set of control experi-
ments were conducted and the results indicated that both the
palladium catalyst and acid were necessary for the present
reaction to proceed (Table 1, entries 12 and 13).
Scheme 2 Catalytic highly regioselective hydroaminocarbonylation of
alkenes.
At the beginning of this study, styrene (1a) and dibenzyl-
amine (2a) were chosen as the benchmark substrates. On the
basis of our previous work,9 NH2OH·HCl was utilized as a co-
catalyst to generate Pd-hydride species via oxidative addition
with Pd(0), which is a key reactive species for initiation of the
desired reaction. The carbonylation reactions were conducted
in the presence of 20 atm of CO with anisole as the solvent at
120 °C for 24 h. Firstly, various palladium catalysts, such as
Pd(Xantphos)Cl2, Pd(PPh3)2Cl2, Pd(PPh3)4 and Pd(t-Bu3P)2
were employed. As expected, Pd(t-Bu3P)2 stood out as the best
catalyst to afford the desired product 3aa in 95% yield with
excellent regioselectivity (B/L > 20 : 1) (Table 1, entry 4). The
pressure of CO is crucial for the reaction, as lower CO pressure
led to reduced yields (Table 1, entries 4–6). The ratio of 1a/2a
was also key for this reaction, the branched amide was isolated
in 95% yield when a higher alkene loading (2 equiv.) was used
(see the ESI†). Other parameters of the reaction conditions,
such as temperature and solvent, were checked and found that
These promising results for the model reaction inspired us
to study the hydroaminocarbonylation of a range of aromatic
alkenes with dibenzylamine (Table 2). The styrenes bearing
electron-donating groups on the phenyl ring gave the corres-
ponding products 3ba–3fa in 75–98% yields with excellent
Table 2 Substrate scope of aromatic alkenesa
Table 1 Optimization of reaction conditionsa
3aa + 4aa b
(%)
Entry [Pd]
Acid
3aa/4aa c
1
2
3
Pd(Xantphos)Cl2 NH2OH·HCl
14
15
1 : 2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(t-Bu3P)2
Pd(t-Bu3P)2
Pd(t-Bu3P)2
Pd(t-Bu3P)2
Pd(t-Bu3P)2
Pd(t-Bu3P)2
Pd(t-Bu3P)2
Pd(t-Bu3P)2
Pd(t-Bu3P)2
—
NH2OH·HCl
NH2OH·HCl
NH2OH·HCl
NH2OH·HCl
NH2OH·HCl
NH2CH2COOH·HCl 55
NH2CH2COOiPr·HCl 43
PhCOOH
CH3COOH
TsOH
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
—
11
4
>99(95)f
24
5d
6e
7
<5
8
9
10
11
12
13
<5
NR
<5
<5
NR
>20 : 1
>20 : 1
—
—
NH2OH·HCl
a Reaction conditions: 1a (0.8 mmol), 2a (0.4 mmol), [Pd] (0.02 mmol),
acid (0.02 mmol), anisole (1.0 mL), CO (20 atm), 120 °C, 24 h. b Yields
were based on amines and determined by GC analysis using n-cetane a Reaction conditions:
1 (0.8 mmol), 2a (0.4 mmol), Pd(t-Bu3P)2
as the internal standard. c The ratio of 3aa/4aa (B/L) was determined by (0.02 mmol), NH2OH·HCl (0.02 mmol), CO (20 atm), anisole (1 mL),
GC analysis. d CO (10 atm). e CO (1 atm). f Isolated yield of 3aa is given 120 °C, 24 h, isolated yield based on amines. The B/L ratio within
in parenthesis.
parentheses was determined by GC and GC-MS analysis. b 30 h.
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regioselectivities. It is noteworthy that the reaction efficiency
of 3- or 4-substituted styrene was better than the 2-substituted
ones (3ca, 3da versus 3ba), which might be attributed to the
steric hindrance effect on the reactivity. Surprisingly, the yield
declined to 29% when a methoxy group was installed on the
benzene ring (3ga). Besides electron-donating groups, elec-
tron-withdrawing groups can also be tolerated in this trans-
formation (71–95% yields, B/L > 20 : 1, 3ha–3ka). However, the
yield and regioselectivity of the corresponding products were
dramatically decreased when the bromine was substituted in
the benzene ring (14% yield, B/L = 0.4 : 1, 3la). Aside from the
styrenes, naphthyl-derived alkene 1m was also compatible with
this process to afford the desired product 3ma in 95% yield
with excellent regioselectivity. Alkenes containing pyridine and
pyrimidine were also suitable for this transformation to
provide the desired products in moderate to good yields with
excellent regioselectivities. It is worth pointing out that the
regioselectivities obtained here are generally much higher
than those reported by others.10 Next, we tried to extend the
scope of the methodology to aliphatic alkenes. The product
3pa could be obtained in good yield with only one isomer
when norfenchene 1p was utilized as the substrate.
Unfortunately, other aliphatic alkenes cannot be applied in the
present catalytic system. Only lower reactivities were observed
for the reaction of enolether and conjugated diene (29% and
18% yield, respectively).
Fig. 1 Plausible reaction mechanism.
amines (2e–2g) still showed higher levels of reactivity towards
this reaction, furnishing the desired products (3ae–3ag) in
good yields. However, the regioselectivities for cyclic amines
were decreased (3ae, 3af and 3ag). The catalytic system is also
effective for aromatic and heterocycle-containing amines,
affording the desired products (3ah–3aj) in good yields with
excellent regioselectivities. However, only a lower yield was
achieved when a primary aliphatic amine was used as a sub-
strate (3ak). To demonstrate the utility of the present reaction,
napropamide, a kind of herbicide, was successfully prepared
in 94% yield with excellent regioselectivity by the reaction of 2-
(vinyloxy)naphthalene with anilines in the presence of CO
under the optimized reaction conditions.
According to the above results and previous mechanistic
investigation on palladium-catalyzed hydroaminocarbonyla-
tion,9,11 we propose that the reaction proceeds via the following
pathways (Fig. 1). Initially, the palladium hydride is produced
via oxidative addition of hydroxylamine hydrochloride to Pd(0),
which reacts with alkenes to generate the alkylpalladium species
A via hydropalladation. Intermediate B is formed through CO
insertion, which undergoes aminolysis leading to the desired
product and regenerates the palladium hydride species.
Once we had identified that aromatic alkenes were ade-
quate substrates for this reaction system, we aimed at expand-
ing the substrate scope to other free aliphatic and aromatic
amines. As shown in Table 3, apart from dibenzylamine, ali-
phatic amines (2b–2d) were also compatible with this reaction
to give the desired branched amides in moderate to good
yields with high regioselectivities (3ab–3ad). Moreover, cyclic
Table 3 Substrate scope of the aminesa
In summary, we have successfully identified that Pd(t-Bu3P)2
could act as an efficient catalyst for promotion of the
hydroaminocarbonylation of aromatic alkenes to branched
amides. By using hydroxylamine hydrochloride as the additive, a
wide range of styrenes and heterocycle-containing alkenes are
efficiently transformed into the corresponding branched amides
in good yields with excellent regioselectivities. In view of this, the
method is expected to complement the current methods for
synthesis of branched amides in synthetic organic chemistry.
Acknowledgements
a Reaction conditions: 1a (0.8 mmol), 2 (0.4 mmol), Pd(t-Bu3P)2
(0.02 mmol), NH2OH·HCl (0.02 mmol), CO (20 atm), anisole (1 mL),
120 °C, 24 h, isolated yield based on amines. The B/L within paren-
theses was determined by GC and GC-MS analysis. b NH2OH·HCl
(0.8 mmol). c CO (40 atm).
This research was supported by the National Natural Science
Foundation of China (21672199), the CAS Interdisciplinary
Innovation Team and the Anhui provincial Natural Science
Foundation (1708085MB28).
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