Palladium-catalyzed hydroaminocarbonylation of alkenes with amines promoted by weak acid

Article abstract of DOI:10.1016/j.tetlet.2015.12.031

The weak acid has been identified as an efficient basicity-mask to overcome the basicity barrier imparted by aliphatic amines in the Pd-catalyzed hydroaminocarbonylation, which enables both aromatic and aliphatic amines to be applicable in the palladium-catalyzed hydroaminocarbonylation reaction. Notably, by using this protocol, the marketed herbicide of Propanil and drug of Fentanyl could be easily obtained in a one-pot manner.

Full text of DOI:10.1016/j.tetlet.2015.12.031

Tetrahedron Letters 57 (2016) 383–386
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed hydroaminocarbonylation of alkenes
with amines promoted by weak acid
a,
Guoying Zhang a,c, Xiaolei Ji a,b, Hui Yu a,c, Lei Yang a,c, Peng Jiao b, , Hanmin Huang
⇑
⇑
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
b College of Chemistry, Beijing Normal University, Beijing 100875, PR China
c University of Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The weak acid has been identified as an efficient basicity-mask to overcome the basicity barrier imparted
by aliphatic amines in the Pd-catalyzed hydroaminocarbonylation, which enables both aromatic and ali-
phatic amines to be applicable in the palladium-catalyzed hydroaminocarbonylation reaction. Notably,
by using this protocol, the marketed herbicide of Propanil and drug of Fentanyl could be easily obtained
in a one-pot manner.
Received 6 November 2015
Accepted 7 December 2015
Available online 10 December 2015
Keywords:
Palladium
Ó 2015 Elsevier Ltd. All rights reserved.
Hydroaminocarbonylation
Alkenes
Amines
Amides
Introduction
As one of the most important fundamental structural motifs,
amide has been considered as a privileged structure in natural
products, pharmaceuticals, pesticides, and functional materials.1
For instance, the core structure of Propanil (herbicide),2 Fentanyl
(potent anesthesia and analgesic drug),3 Flutamide (antiandrogen
drug),4 and Bucinnazine (potent analgesic drug)5 is amide
(Scheme 1). Therefore, the development of sustainable and atom-
economic method for the synthesis of amides continues attracting
much interest in academic research and industrial chemistry.
Driven by this prevalence, various methods have been devel-
oped for the synthesis of amides in recent decades.6,7 One of the
most promising methods is hydroaminocarbonylation of simple
alkenes with amines in the presence of CO, which represents an
ideal and atom economic approach to amides without formation
of any by-products. Various catalysts, such as Ru, Rh, Pd, Co, and
Ni complexes, have been reported for this method.8 However, to
the best of our knowledge, these reported methods suffer from
forcing reaction conditions and only being applicable for aromatic
amines. As for the palladium-catalyzed system, the conceivable
reasons for the dependence of reactivity on nature of amines might
be attributed to the fact that the key Pd-hydride catalytic species
only can survive under relatively acidic conditions.8 To circumvent
Scheme 1. Amide-containing pesticide and pharmaceuticals.
this substrate inhibition, we developed a ternary catalyst system
composed of Pd/acid/paraformaldehyde effective for the conver-
sion with both aromatic amines and aliphatic amines, in which
the paraformaldehyde was utilized to mask the basicity of aliphatic
amines to facilitate producing the key active Pd–H species.9
Inspired by this result and in connection with our interests in the
carbonylation reactions,10 we present herein a practical and effi-
cient palladium-catalytic system for the hydroaminocarbonylation
of simple alkenes with both aromatic and aliphatic amines under
CO atmosphere, thus allowing the synthesis of the linear amides
with high selectivity (Scheme 2). The stoichiometric amount of
weak acid used in this catalytic system has been identified as an
effective basicity-mask to overcome the basicity barrier imparted
by the aliphatic amines and thus facilitating the hydroaminocar-
bonylation. Notably, in a one-pot manipulation, the Propanil and
⇑
Corresponding authors.
E-mail addresses: pjiao@bnu.edu.cn (P. Jiao), hmhuang@licp.cas.cn (H. Huang).
http://dx.doi.org/10.1016/j.tetlet.2015.12.031
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

384
G. Zhang et al. / Tetrahedron Letters 57 (2016) 383–386
Scheme 2. Catalytic hydroaminocarbonylation of alkenes.
Fentanyl can be obtained in gram scale with high yields from sim-
ple ethene and corresponding amines.
Results and discussion
On the basis of our experience with palladium catalyzed
hydroaminocarbonylation reactions, styrene (1a) and dibenzy-
lamine (2a) were chosen as model substrates, and the reaction
was performed under 10 atm of CO at 120 °C for 24 h. With DPPPen
as the ligand and [Pd(allyl)Cl]2 as the catalyst precursor, the reac-
tion proceeded well in the presence of one equivalent of NH2-
OHÁHCl to give the desired amide in 89% yield with relatively
lower regioselectivity (Table 1, entry 1). Encouraged by this result,
various phosphine ligands were examined (Table 1, entries 2–9)
and it was found that Xantphos was the most effective, affording
99% yield of the desired products with good regioselectivity. Next,
various acids were evaluated. Only a trace amount of the product
was detected when organic acids, such as HCO2H, CH3CO2H, and
NH2CH2CO2H served as additives (Table 1, entries 10–12). In addi-
tion, other acids such as TsOH, NH2CH2CO2MeÁHCl, NH(Me)(OMe)Á
HCl, and NEt3ÁHCl did not improve the reactivity and regioselectiv-
ity for this carbonylation reaction (Table 1, entries 13–17). Finally,
control experiments revealed that both the palladium catalyst and
acid are essential to this reaction (Table 1, entry 18).
Scheme 3. Scope of aromatic alkenesa. aReaction conditions: 1 (1.0 mmol), 2a
(0.5 mmol), [Pd(allyl)Cl]2 (0.01 mmol), Xantphos (0.025 mmol), NH2OHÁHCl
(0.5 mmol), anisole (2.0 mL), CO (10 atm), 120 °C, 24 h. Isolated of 3; the L/B within
parentheses were determined by GC and GC–MS analyses. bGram scale.
halogen groups, were suitable to give the corresponding products
3aa–3ja in good to excellent yields with high regioselectivity.
The ortho-substituted alkenes exert positive effect on the reactivity
With the optimized reaction conditions established, substrate
scope of the styrenes was first investigated and the results are
summarized in Scheme 3. Styrenes with various substituents on
the para-, meta-, and ortho-positions, such as alkyl-, alkoxy-, and
Table 1
Optimization of reaction conditionsa
Entry
Ligand
Acid
3 + 4 (%)b
3/4c
1
2
3
4
5
6
7
8
DPPPen
DPPB
DPPH
BINAP
NH2OHÁHCl
NH2OHÁHCl
NH2OHÁHCl
NH2OHÁHCl
NH2OHÁHCl
NH2OHÁHCl
NH2OHÁHCl
NH2OHÁHCl
NH2OHÁHCl
HCO2H
89
<5
76
<5
49
99
99
<5
<5
8
70:30
—
33:65
—
84:16
88:12
84:16
—
DPEphos
Xantphos
NiXantphos
t-BuXantphos
d
9
PPh3
—
10
11
12
13
14
15
16
17
18
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
77:23
72:28
88:12
88:12
77:23
88:12
82:18
75:25
—
CH3CO2H
NH2CH2CO2H
TsOH
7
5
43
82
65
82
23
<5
NH2SO3H
NH2CH2CO2MeÁHCl
NH(Me)(OMe)ÁHCl
NEt3ÁHCl
—
a
Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), [Pd(allyl)Cl]2 (0.01 mmol),
ligand (0.025 mmol), acid (0.5 mmol), anisole (2.0 mL), CO (10 atm), 120 °C, 24 h.
Scheme 4. Scope of aliphatic alkenes. Reaction conditions:
5 (1.0 mmol), 2a
b
Yields were determined by GC analysis using n-cetane as the internal standard.
The ratios of 3aa:4aa (L/B) were determined by GC and GC–MS analyses.
(0.5 mmol), [Pd(allyl)Cl]2 (0.01 mmol), Xantphos (0.025 mmol), NH2OHÁHCl
(0.5 mmol), anisole (2.0 mL), CO (10 atm), 120 °C, 24 h. Isolated of 6; the L/B within
parentheses were determined by GC and GC–MS analyses.
c
d
PPh3 (0.05 mmol).

G. Zhang et al. / Tetrahedron Letters 57 (2016) 383–386
385
smoothly to give the desired product in 98% yield under 5 atm
of ethene. Alkyl substituted olefins with long chain 5b–5g were
suitable for the reaction to give products 6ba–6ga in 82–84%
yields. Other olefins bearing functional groups, such as chloro,
ketone, nitrile, and ester, could be successfully transferred to
the desired products 6ha–6la in good yields. It is worth noting
that the tolerance of halogens, ketone, and ester functional-group
in this carbonylation reaction offers an opportunity for further
transformations, which facilitates expedient synthesis of complex
amides. As exemplified by reactions of 4-vinylcyclohex-1-ene
(5m) and (+)-b-citronellene (5n), the hydroaminocarbonylation
reaction took place exclusively at the terminal double bond of
dienes to give the corresponding linear amides 6ma and 6na in
excellent yields, while the internal double bond remained intact.
However, the hydroaminocarbonylation of norbornene (5o) pro-
ceeded well under the same reaction condition to give the exo-
product in 83% yield (Fig. 1, right) (determined by X-ray analysis,
see Supporting information).11
The subsequent study was focused on substrate scope of
amines. As summarized in Table 2, various amines were found to
be tolerated in this carbonylation process. For example, several
secondary aliphatic amines, such as dibenzylamine, dipropy-
lamine, dibutylamine, and N-benzylpropan-1-amine were effective
substrates to react with tetradec-1-ene smoothly to afford corre-
sponding amides in good to excellent yields with high regioselec-
tivity (70–87% yields). Moreover, typical cyclic amines including
piperidine, morpholine, as well as 1,2,3,4-tetrahydroisoquinoline
were well tolerated in this transformation, giving corresponding
amides in good yields (6df–6dh), respectively. Not surprisingly,
the hydroaminocarbonylation reaction with the primary aliphatic
amines proceeded smoothly, offering the corresponding amides
in good yields (6di and 6dj). Compared to the aliphatic amines,
the anilines proceed smoothly in the presence of catalytic amount
of acid, producing the desired products 6dk and 6dl in good yields,
respectively.
Figure 1. X-ray of Propanil (left) and 6oa (right).
Table 2
Optimization of reaction conditionsa
Entry
R1, R2
6
Yield (%)
L/B
1
2
3
4
5
6
7
8
R1 = R2 = Bn
6da
6db
6dc
6dd
6de
6df
6dg
6dh
6di
84
87
70
72
70
64
78
55
73
68
72
82
87:13
95:5
R1 = R2 = (4-ClC6H4)CH2
R1 = R2 = n-Pr
86:14
85:15
83:17
81:19
85:15
88:12
90:10
80:20
78:22
87:13
R1 = R2 = n-Bu
R1 = Bn, R2 = n-Pr
R1, R2: piperidyl
R1, R2: morpholyl
R1, R2: tetrahydroisoquinolyl
R1 = Bn, R2 = H
9
10
11b
12b
R1 = n-Bu, R2 = H
R1 = Ph, R2 = H
6dj
6dk
6dl
R1 = 3,4-Cl2C6H3, R2 = H
a
Reaction conditions: 5 (1.0 mmol), 2 (0.5 mmol), [Pd(allyl)Cl]2 (0.01 mmol),
Xantphos (0.025 mmol), NH2OHÁHCl (0.5 mmol), anisole (2.0 mL), CO (10 atm),
120 °C, 24 h. Isolated of 6; the L/B within parentheses were determined by GC and
GC–MS analyses.
b
NH2OHÁHCl (0.05 mmol).
and selectivity to afford the liner products in excellent yields with
high regioselectivity (3da and 3ja). It was noteworthy that the
reactions with halo-substituted alkenes performed smoothly to
give the corresponding amides in 79–89% yields with good regios-
electivity (3ga–3ja), which could be used for further transforma-
tions. Moreover, 2-vinylnaphthalene also provided the desired
liner product 3la in a good yield under the current reaction condi-
tion. Inspired by these results, we turn our attention to the vinyl-
heteroarenes. Surprisingly, when 4-vinylpyridine (1k) was
employed as the coupling partner, the corresponding branched
product 3ka was obtained as the major product in 60% isolated
yield under standard condition. Importantly, this transformation
was successful for gram-scale (2.51 g) preparation, giving a compa-
rable yield (76%) by using a much lower amount of catalyst
(0.1 mol %).
The practice and convenience of this novel method to amides
can be readily applied in the synthesis of amide-containing herbi-
cide and pharmaceutical. As shown in the Scheme 5, the herbicide
Propanil can be effectively assembled from simple ethene, 3,4-
dichloroaniline (2l), and CO on a gram scale in the presence of
0.1 mol % palladium catalyst and 10 mol % of weak acid. This
approach represents
a highly atom-economical and efficient
(TON = 375) protocol for the synthesis of Propanil amide from
the simple staring materials. The structure of Propanil was con-
firmed by single-crystal X-ray diffraction analysis (Fig. 1, left).11
Fentanyl is a potent, synthetic opioid analgesic with a rapid onset
and short duration of action, which approximately 80–100 times
more potent than morphine.3 With the newly developed catalytic
system, Fentanyl was prepared in gram scale (1.5 g) by
hydroaminocarbonylation of ethene with 1-phenethyl-N-phenyl-
piperidin-4-amine (2m) under 5 atm of CO atmosphere in the pres-
ence of 0.1 mol % palladium catalyst. The desired pharmaceutical
Fentanyl isolated in 96% yield.
To further explore the synthetic potential of this process, a
series of more challenging aliphatic alkenes were subjected to
this reaction under the same reaction condition (Scheme 4). To
begin with, ethene was employed and the reaction performed
Scheme 5. One-pot synthesis of Propanil and Fentanyl.

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G. Zhang et al. / Tetrahedron Letters 57 (2016) 383–386
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In summary, we have successfully developed a practical palla-
dium catalytic system for the hydroaminocarbonylation reaction
of simple alkenes with both aliphatic and aromatic amines under
CO atmosphere. The weak acid was found to be an effective basic-
ity-mask to promote the desired reaction. The catalysis accommo-
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Acknowledgments
This research was supported by the Chinese Academy of
Sciences and the National Natural Science Foundation of China
(21222203, 21372231 and 21133011).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.12.
031.
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