Metal-catalyzed formal amidation of alkenes under CO-free condition

Article abstract of DOI:10.1016/j.tetlet.2016.08.007

An effective procedure for synthesis of amides from alkenes and [Formula presented] via Pd and Fe catalysts under mild conditions is described. A series of benzamides containing various functional groups can be obtained in reasonable yield and the possible reaction pathway is proposed in this Letter.

Full text of DOI:10.1016/j.tetlet.2016.08.007

Accepted Manuscript
Metal-catalyzed formal amidation of alkenes under CO-free condition
Yuanyuan Zhang, Wenjing Ye, Xue Leng, Ying He, Hui Zhang, Xiao Xiao
PII:
S0040-4039(16)30994-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.007
TETL 47978
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 June 2016
23 July 2016
3 August 2016
Please cite this article as: Zhang, Y., Ye, W., Leng, X., He, Y., Zhang, H., Xiao, X., Metal-catalyzed formal amidation
of alkenes under CO-free condition, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.08.007
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Metal-catalyzed formal amidation of alkenes
under CO-free condition
Leave this area blank for abstract info.
Yuanyuan Zhang, Wenjing Ye, Xue Leng,
Ying He, Hui Zhang* and Xiao Xiao*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Metal-catalyzed formal amidation of alkenes under CO-free condition
Yuanyuan Zhang, Wenjing Ye, Xue Leng, Ying He, Hui Zhang* and Xiao Xiao*
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
ARTICLE INFO
ABSTRACT
Article history:
Received
An effective procedure of synthesis of amides from alkenes and PhI=NTs via Pd and Fe
catalysts under mild conditions is described. A series of benzamides containing various
functional groups can be obtained in reasonable yield and the possible reaction pathway is
proposed in this paper.
Received in revised form
Accepted
Available online
2016 Elsevier Ltd. All rights reserved
.
Keywords:
Amidation of alkenes
CO-free
Metal catalysis
PhI=NTs
Cascaded reaction
Amides as the important building blocks in natural products and the fundamental structural motifs of peptides play a crucial role
in organic chemistry and pharmaceutical chemistry as well as biological chemistry.1 Typically amides can be obtained by the
coupling reaction of highly activative acid derivatives with corresponding amines via coupling reagents.2 However, additional
preparation and unstability of acid derivatives make the synthesis of amides more complicated. During the past decades, the highly
efficient synthesis of amides has attracted considerable interest from chemists, such as oxidative amidation of alcohols and
aldehydes3, aminocarbonylation of organohalides4, alkenes5, and alkynes6, oxidation of amines7, rearrangement reaction8, and so
on.9
The transition-metal-catalyzed aminocarbonylation of simple alkenes with amines and CO is a straightforward method
to convert a carbon-carbon double bond into an amide bond, which generally suffers from high temperature and air
pressure.5 To the best of our knowledge, only two examples reported CO-free oxidative amidation of terminal alkenes via
oxidants TBHP or I2.10 Therefore it is still significant to develop new protocols for the amidation of alkenes under mild
condition. During our studies, we have found that benzaldimines (
2) and benzaldehydes (3) can be obtained from stilbenes
(1
) catalyzed by Pd with PhI=NTs as nitrogen donor. Recently, Chan11 reported Fe-catalyzed amidation of aldehydes using
the same iminoiodinane as nitrogen source.12 Inspired by Chan’s work, we proposed a sequential procedure catalyzed by
palladium and iron respectively, using PhI=NTs as nitrogen transfer reagent at room temperature, which presented a
formal amidation of alkenes (Scheme 1).

3
Scheme 1. Design of one-pot amidation of stilbenes.
Initially, trans-stilbene (1a), PhI=NTs, and Pd catalyst were stirred for 6 hours to generate benzaldimine (2a) which
would be hydrolyzed to benzaldehyde (3a) in the presence of trace amounts of H2O in air. Subsequently, FeCl2 and
Pyridine were added to the mixture, giving amide 4a as the final product. The efficiency of the in situ process might be
highly dependent on the balance among benzaldimine (2a) and benzaldehyde (3a) (Scheme 1). As shown in Table 1,
various Pd catalysts were firstly screened in the reaction of trans-stilbene with PhI=NTs. Amide 4a could be obtained in
52-60% yields catalyzed by Pd (0) such as, Pd2(dba)3, Pd(dba)2, and Pd(PPh3)4 (entries 1-3, Table 1). Among Pd(II)
catalysts, PdCl2 gave the highest activity (62% yield) (entry 5, Table 1) while PdBr2, Pd(acac)2, and (η3-C3H5PdCl)2
catalyzed the cascaded reaction in similar efficiency (entries
Table 1
Optimization of reaction conditionsa
Entry
1
Condition
Pd2(dba)3, L2 = py, CH2Cl2
Pd(dba)2, L2 = py, CH2Cl2
Pd(PPh3)4, L2 = py, CH2Cl2
Pd(OAc)2, L2 = py, CH2Cl2
PdCl2, L2 = py, CH2Cl2
Yield (%)b
52
2
56
3
60
4
26
5
62
6
PdBr2, L2 = py, CH2Cl2
53
7
(η3-C3H5PdCl)2, L2 = py, CH2Cl2
Pd(COD)Cl2, L2 = py, CH2Cl2
Pd(acac)2, L2 = py, CH2Cl2
PdCl2, L1 = PPh3, L2 = py, CH2Cl2
PdCl2, L1 = dppf, L2 = py, CH2Cl2
PdCl2, L1 = dppp, L2 = py, CH2Cl2
PdCl2, L1 = dppe, L2 = py, CH2Cl2
PdCl2, L2 = DMAP, CH2Cl2
PdCl2, L2 = 2-picolinic acid, CH2Cl2
PdCl2, L2 = Ph-pybox, CH2Cl2
PdCl2, L2 = 1,10-phenanthroline, CH2Cl2,
PdCl2, L2 = py, CHCl3
53
8
31
9
59
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24c
25d
26c,e
27f
25
29
28
25
32
35
46
14
66
PdCl2, L2 = py, ClCH2CH2Cl
PdCl2, L2 = py, Toluene
54
34
PdCl2, L2 = py, THF
40
PdCl2, L2 = py, DMF
12
PdCl2, L2 = py, 1,4-Dioxane
PdCl2, L2 = py, MeOH
36
-
PdCl2, L2 = py, CHCl3
trace
-
PdCl2, L2 = py, CHCl3
PdCl2, L2 = py, CHCl3
16
a
All reactions were carried out with trans-stilbene (0.50 mmol), PhI=NTs (2.0 mmol), Pd catalyst (0.050 mmol), L1 (0.10 mmol), FeCl2 (0.050
mmol), and L2 ( 0.20 mmol) in solvent (2.0 mL) at rt.
b Isolated yield.
c The product amide 4a was not dectected. d Reaction temperature was 40 oC.
e Reaction temperature was 0 oC.
d PhI=NTs was replaced by PhI(OAc)2 (2.0 mmol) and TsNH2 (2.0 mmol).
6,7,and 9, Table 1). Lower product yields (26% and 31%) were found when Pd(OAc)2 and Pd(COD)Cl2 were used as
catalysts ( entries 4 and 8, Table 1). Several phosphite ligands were also screened in the Pd catalyzed process. However
the reaction efficiency was obviously decreased (entries 10-13, Table 1). On the other hand, a series of nitrogen-
containing ligands were applied in FeCl2 catalyzed amidation of aldehydes, furnishing 4a in 14-46% yields (entries 14-17,
Table 1). Therefore pyridine was still the most suitable ligand for FeCl2. Further optimization of reaction condition was
carried out with PdCl2 as catalyst. Different solvents were tested in the amidation of stilbene. Higher yields could be

obtained in haloalkanes (enties 18-19, Table 1), which were identical with chan’s report11. In other solvents, imine 2a was
produced in small amounts and N-tosylbenzamide (4a) was afforded in 12-40% yields (enties 20-23, Table 1). No imine
and corresponding amide could be detected by TLC using MeOH as a solvent (entry 24,
Table 2
Scope of the substituted stilbenes of PdCl2 and FeCl2 catalyzed amidation.a
Entry
R
Product(
4a
4)
Yield (%)b
1
2c
p-
H
66
64
p-H (cis)
4a
3
4c
p-CO2Me
p-CO2Me (cis)
p-Ph
4b
4b
4c
4d
4e
4f
51
56
49
62
47
49
60
72
75
63
67
71
68
5
6
p-Br
7
p-OMe
o-Me
8
9
m
-Me
4g
4h
4i
10
11
12
13
14
15
p-Me
p-Et
p-nBu
p-iBu
4j
4k
4l
p-nAmyl
p-nHexyl
4m
a
All reactions were carried out with stilbenes (0.50 mmol), PhI=NTs (2.0 mmol), PdCl2 (0.050 mmol), FeCl2 (0.050 mmol), and pyridine (0.20
mmol) and in CHCl3 (2.0 mL).
b Isolated yield.
c Cis olefin was used.
Table 1). Higher temperature was negative for the FeCl2-catalyzed second step, giving trace amide (entry 25, Table 1). On
the other hand, imine 2a could not be obtained at lower temperature, so no desired amide product was isolated when the
o
reaction temperature was 0 C (entry 26, Table 1). It is worth to mention that the amidation reaction with PhI(OAc)2 and
TsNH2 as nitrogen source proceeded less effectively to furnish the product 4a in 16% yield (entry 27, Table 1).
Under the optimal reaction conditions, the scope of PdCl2 and FeCl2 catalyzed amidation of substituted stilbenes was
examined. As summarized in Table 2, the reaction could
proceed smoothly with various substituted stilbenes affording the corresponding N-tosylbenzamides in 47-75% yields.
The exploration of geometric isomers’ activities indicated that there was no obvious distinction between trans and cis
olefins (entries 1-4, Table 2). Stilbenes with electron-withdrawing functional groups at para position of the aromatic gave
the amide products in 49-62% (entries 3-6, Table 2). The fact that 4-methoxybenzaldehyde was not an efficient substrate
for the FeCl2 catalyzed process11 led to the low reactivity of the 4,4’- dimethoxyl stillbene (entry 7, Table 2). Ortho and
meta-methyl substituted N-tosylbenzamides (4f and 4g) were obtained in lower yields than the para-methyl substituted one
(4h) which was perhaps due to the larger steric hinderance of stilbenes 1f and 1g (entries 8-10, Table 2). The substrates
with alkyl groups were able to be nicely tolerated in the reaction, giving the desired amides 4i-m in 63-75% yields (entries
11-15, Table 2).
The amidation of stilbenes with different para-substituents on benzene ring was also examined, affording two
corresponding imides (entries 1-2, Table 3). P-methoxylbenzamide 4e could be obtained in lower product
Table 3
Scope of the substituted alkenes of PdCl2 and FeCl2 catalyzed amidation.a
b
Substrate(
1
)
Product(4)

5
R1 = Ph,
R2 =
p-OMePh; (1n)
R1 =
R2 =
p
-BrPh,
p-OMePh; (1o
)
R1 = R2 = n-Bu; (1p
)
R1 = Ph,
R2 = CH3; (1q
)
a
All reactions were carried out with alkene (0.50 mmol), PhI=NTs (2.0 mmol), PdCl2 (0.050 mmol), FeCl2 (0.050 mmol), and pyridine (0.20
mmol) and in CHCl3 (2.0 mL).
b Isolated yield.
yield than benzamide 4a and p-bromobenzamide 4d. Unfortunately, under standard condition the amidation reaction
couldn’t proceed as aliphatic olefin was used (entry 3, Table 3), which was also supported by the fact that the benzamide
4a was the only product in the amidation of phenylpropylene (1n) (entry 4, Table 3).
Some control experiments were carried out for the mechanistic study of the Pd-catalyzed cracking of alkenes (Scheme
2). Equivalent PdCl2 was used respectively to react with stilbene (1a) or PhI=NTs for 3 hours before the other material
was added. Under the same reaction conditions, the reaction (1) proceed smoothly, giving N-tosylbenzamides and
1
benzaldehyde in 78% H NMR yield as well as trace aziridine 5a and triphenylcyclopropane 6a, while the reaction (2)
was inefficient with a large amount of remaining stilbene in the crude product mixture. Those experiments
Scheme 2. Control experiments for mechanistic study.

Scheme 3. Proposed reaction pathway for the amidation of alkenes.
indicated that the Pd catalyst might firstly react with stilbene to generate metal-alkene complex which was likely
necessary for the reaction. Furthermore, relatively electron-rich aliphatic olefin might be unable to coordinate with PdCl2,
so no amide product was obtained when 5-decene was used as the substrate (entry 3, Table 3).
Based on the aforementioned observations, a plausible reaction pathway for the PdCl2 and FeCl2 catalyzed amidation of
alkenes is proposed in Scheme 3. Pd-alkene complex
which will form compound . The four-membered ring
or imine (Scheme 2). Compound 10, which can be captured by stilbene
another product of elimination path (II) will react with PhI=NTs to regenerate Palladium-nitrogen species
membered ring 11 as intermediate. The C-H bond of arylaldehyde hydrolyzed from imine in air is inserted by an iron-
7
reacts with PhI=NTs to generate Palladium-nitrogen species
will undergo two types of ring-opening, affording aziridine 713
to produce cyclopropane (Scheme 2), as
with four-
8
9
9
2
1
6
8
3
2
11
nitrenoid species 14 to furnish the amide product 4.
In summary, we have developed a novel CO-free formal amidation of alkenes catalyzed by palladium and iron with
PhI=NTs as nitrogen source at room temperature. Benzamides with various functional groups can be afforded in moderate
yield. The current method provides a straightforward and effective approach to synthesize arylamides from substituted
stilbenes, which consist of palladium-catalyzed transformation of carbon-carbon double bond to carbon-nitrogen double
bond and iron-catalyzed amidation of aldehydes. Further studies will be devoted to
developing more effective catalytic systems to expand substrate scope as well as deeply exploring the reaction mechanism.
Acknowledgments
We gratefully acknowledge the Natural Science Foundation of China (No.21402127) and the Career Development
Support Plan for Young and Middle-aged Teachers in Shenyang Pharmaceutical University for the financial support.
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Graphical Abstract
Metal-catalyzed formal amidation of alkenes
under CO-free condition
Yuanyuan Zhang, Wenjing Ye, Xue Leng,
Ying He, Hui Zhang* and Xiao Xiao*

9
Manuscript Title: Metal-Catalyzed Formal
Amidation of Alkenes under CO-Free Condition.
Author Name: Yuanyuan Zhang, Wenjing Ye, Xue Leng, Ying
He, Hui Zhang* and Xiao Xiao*
Highlights
ꢀ
ꢀ
ꢀ
A novel metal-catalyzed formal amidation of alkenes
without CO and oxidant is developed.
A various of substituted benzamides can be
synthesized in reasonable yield
The cascaded reaction involves oxidative cleavage
of alkenes and amidation of aldehydes.