Pd-Catalyzed Three-Component Reaction of Anilines, Ethyl Vinyl Ether, and Nitro-Paraffin: Assembly of β-Nitroamines

Article abstract of DOI:10.1021/acs.orglett.7b03631

A novel palladium-catalyzed amination and nitration of ethyl vinyl ether for the construction of β-nitroamine derivatives under mild conditions has been developed. This transformation provides a new strategy for the installation of amino and nitro from aromatic amines and nitro-paraffin into alkenes. Morpholine resulted in the aza-Henry reaction, while DABCO led to the unexpected rearrangement.

Full text of DOI:10.1021/acs.orglett.7b03631

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Three-Component Reaction of Anilines, Ethyl Vinyl
Ether, and Nitro-Paraffin: Assembly of β‑Nitroamines
Lu Ouyang, Lingzhi Zhan, Jianxiao Li, Qiaoyu Zhang, Chaorong Qi, Wanqing Wu,*
and Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A novel palladium-catalyzed amination and
nitration of ethyl vinyl ether for the construction of β-
nitroamine derivatives under mild conditions has been
developed. This transformation provides a new strategy for
the installation of amino and nitro from aromatic amines and
nitro-paraffin into alkenes. Morpholine resulted in the aza-
Henry reaction, while DABCO led to the unexpected
rearrangement.
Scheme 1. Pd-Catalyzed Oxidative Amination of Alkenes and
aza-Henry Reaction
ulticomponent reactions (MCRs) are convergent, facile,
Mand efficient reactions, in which a small set of starting
materials react to build up the final product according to
cascade chemical reactions with minimal workup, high atom-
economy, and experimental simplicity.1 Thus, they have been
one of the most interesting and promising synthetic methods,
and they provide a facile and efficient protocol to increasing
molecular diversity and complexity. In recent decades,
transition-metal-catalyzed MCRs have been explored inten-
sively and gained outstanding achievements, especially for
palladium catalysis.2
β-Nitroamines containing two nitrogenated functions
represent a class of rather valuable synthons for the
construction of various functional molecules which are
important in bioactive molecules, pharmaceuticals agents, and
natural products, such as 1,2-diamines and α-aminocarbonyls.3
Our strong interest in the Pd-catalyzed amination of alkenes for
the formation of carbon−carbon and carbon−nitrogen bonds4
and the great value and usefulness of β-nitroamines prompted
us to explore Pd-catalyzed amination and nitration of alkenes
under mild conditions. The aza-Henry reaction (nitro-Mannich
reaction) is a powerful synthetic transformation, which offers an
entry to various functional compounds with amino and nitro
groups (Scheme 1, eq 2).5 Despite significant progress made in
this area in recent decades, most of the direct aza-Henry
reactions started with imines (particularly for electron-deficient
imines) which are ready-made or synthesized by the
condensation of amines and aldehydes.6 To our knowledge,
no studies have addressed the aza-Henry reactions which were
conducted with imines generated in situ from a reaction
between amines and vinyl ethers. Therefore, a new type of aza-
Henry reaction that proceeds with simple and readily available
materials with high efficiency and step-economy is still in
demand. Herein, we disclose a new Pd-catalyzed aza-Henry
reaction between amines, ethyl vinyl ethers, and nitro-paraffin
to form β-nitroamines with simple operations (Scheme 1, eq
3). The imines serving as an intermediate were generated in situ
by the reaction between anilines and ethyl vinyl ethers, which
was seldom reported previously.7
To initiate our study, CH3NO2 3a masked as the nitro group,
aniline 1a selected as the amino group, and ethyl vinyl ether 2a
were examined as potential coupling partners. To our delight, a
29% yield of the desired product 4a was obtained when using
10 mol % of PdCl2 as the catalyst and 1 equiv of AgOAc in
CH3NO2 at 60 °C for 12 h (Table 1, entry 1). We next
Received: November 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03631
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
yield (%)
entry
[Pd]
PdCl2
[Ag]
base
4a
5a
1
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgNO3
Ag2O
−
−
−
−
−
−
−
−
29
41
37
53
31
28
31
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d
29
2
Pd(PPh3)2Cl2
Pd(PhCN)2Cl2
[PdCl(allyl)]2
Pd(TFA)2
3
4
5
6
Pd(cy)3
7
Pd(PPh3)4
8
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
trace
trace
trace
36
9
−
−
KOAc
10
11
12
13
14
15
16
17
18
19
20
21
22
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
KI
31
29
K2CO3
Na2CO3
Cs2CO3
t-BuOK
piperidine
21
22
44
23
trace
trace
71
trace
trace
5
N,N-diisopropyl ethylamine
morpholine
47
20
75
5
ce
,
morpholine
85 (83)
9
6
DABCO
59
de
,
DABCO
7
71 (65)
a
Reaction conditions: all reactions were performed with 1a (0.25 mmol), 2a (2 equiv), palladium catalyst (10 mol %), Ag salts (1 equiv), base (1
b
c
equiv), CH3NO2 (3a, 1 mL), at 60 °C under air for 12 h. Yield was determined by GC with dodecane as internal standard based on 1a. 0.5 equiv of
AgOAc and 0.5 equiv of morpholine were used for 2 h. 0.5 equiv of AgOAc and 0.2 equiv of DABCO were used for 12 h. Isolated yield. n.d. = not
determined.
d
e
examined the palladium catalysts, and [PdCl(allyl)]2 proved to
be the most efficient, which offered 4a in 53% yield (Table 1,
entries 2−7). Using [PdCl(allyl)]2 as the catalyst, different Ag
salts (Table 1, entries 8−10) were examined and AgOAc was
observed to be superior to AgNO3, Ag2O, and Ag2CO3.
Interestingly, when different bases were added, the rearrange-
ment product 5a was detected. Inorganic bases, such as KOAc,
KI, K2CO3, and Na2CO3, gave moderate conversions, and the
ratio of 4a and 5a was between 1:1 and 2:1 (Table 1, entries
11−14). Increasing the basicity by using Cs2CO3 and t-BuOK
resulted in a dramatic drop in conversion as well as yields
(Table 1, entries 15−16). Compared with inorganic bases,
organic bases including piperidine, N,N-diisopropylethylamine,
and morpholine, showed effective selectivity for 4a when
subjected to the reaction conditions (Table 1, entries 17−19),
and morpholine exhibited the highest conversion and
selectivity. By decreasing the amount of AgOAc and morpho-
line to 0.5 equiv, 4a could be obtained in 85% yield (Table 1,
entry 20). Moreover, it is worth noting that when DABCO was
tested in the reaction, the rearrangement product 5a could be
afforded in high selectivity and moderate yield (Table 1, entries
21−22), and conducting the reaction with 0.5 equiv of AgOAc
and 0.2 equiv of DABCO resulted in a 71% yield. Finally, in the
absences of silver salt, neither 4a nor 5a could be examined in
this catalyst system, demonstrating the key role of Ag salts.
With the optimal conditions in hand, a variety of β-
nitroamines were synthesized from amines, ethyl vinyl ether,
and nitro-paraffin using the Pd-catalyzed intermolecular three-
component amination and nitration reaction. Gratifyingly, as
shown in Scheme 2, this morpholine-controlled transformation
was successfully performed on a 0.25 mmol scale to afford α-
alkyl-β-nitroamines. Various arylamines with electron-donating
or -withdrawing groups such as fluoro, chloro, bromo,
trifluoromethyl, isopropyl, and tert-butyl groups were well
tolerated in this catalytic system, and the corresponding α-alkyl-
β-nitroamines 4b−4g were generated in moderate to good
yields. In addition, disubstituted anilines such as 3,5-dimethyl
(1h), 3,4-difluoro (1i), and 3-chloro-4-fluoro aniline (1j) were
found to be compatible with the reaction in the yield of 72%
and 71%. To further explore the steric-hindrance effect of this
Pd-catalyzed amination and nitration, the methyl-substituted
anilines (para-, meta-, and ortho-) were subjected to the
reaction. Unfortunately, the yield was found to be decreased
gradually (4k−4m), which indicated that the steric effect was
obvious. Interestingly, when nitroethane 3b and 1-nitropropane
(3c) were treated as the solvent with aniline under the standard
conditions, the desired products 4n and 4o could be afforded in
moderate yields with a dr ratio of about 1.8:1 and 4.4:1.
However, no desired products were obtained when 2-
nitropropane (3d) and (nitromethyl)benzene 3e served as
solvent. Moreover, enol ethers with different alkoxy groups
were compliant with this reaction and yield the same product
4a.
We next investigated the substrate scope of the [PdCl-
(allyl)]2/DABCO catalytic system (Scheme 3). Various anilines
with fluoro, iPr, and 3,5-dimethyl substituents were subjected to
the optimized reaction conditions, and the corresponding β-
methyl-β-nitroamines 5a−5d were delivered in 60−72% yields.
B
DOI: 10.1021/acs.orglett.7b03631
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Morpholine Controlled Amination and Nitration
of Ethyl Vinyl Ether
Scheme 5. Control Experiments
a
alkyl-β-nitroamines 4 were generated in no more than 2 h, and
β-methyl-β-nitroamines 5 were obtained after 2 h. Then we
carried out further experiments to explain the transformation
between 4 and 5. First, no reaction occurred in the absence of
the Pd catalyst under condition B (Scheme 5, eq 1). When 4a
was subjected to the standard condition B, 5a was produced in
43% yield (Scheme 5, eq 2). Moreover, when the reaction
proceeded without an organic metal reagent or base, 45% yield
of 5a was still achieved (Scheme 5, eq 3). It is worth noting that
when 0.2 equiv of DABCO was added, the transformation
efficiency improved (eq 4), which indicated that DABCO
played an important role in rearrangement process. To further
probe the transformation between 4 and 5, some control
experiments were carried out under standard condition B
(Figure 1). As the reaction time was prolonged, the yield of 4a
a
Reaction condition A: all reactions were performed with amines 1
(0.25 mmol), ethyl vinyl ether 2a (2 equiv), [PdCl(allyl)]2 (10 mol
%), AgOAc (0.5 equiv), morpholine (0.5 equiv), nitro-pataffin (3, 1
mL), at 60 °C under air for 2 h. Yields refer to isolated yield. Reaction
b
for 4 h.
Scheme 3. DABCO Controlled Amination and Nitration of
Ethyl Vinyl Ether
a
a
Reaction condition B: all reactions were performed with amines 1
(0.25 mmol), ethyl vinyl ether 2a (2 equiv), [PdCl(allyl)]2 (10 mol
%), AgOAc (0.5 equiv), DABCO (0.2 equiv), CH3NO2 (3a, 1 mL), at
60 °C under air for 12 h. Yields refer to isolated yield.
Figure 1. Time course of controlling experiments.
was initially increased and began to decrease after 2 h (orange).
But 2 h later, 5a was generated and the yield continued to
increase to 79% (gray). These interesting results suggested that
4 could be converted to 5 under this catalytic system.
Based on these interesting phenomena and findings, the
proposed mechanistic pathway of this palladium-catalyzed
amination and nitration is shown in Scheme 6. First, imine I
Simultaneously, steric hindrance clearly has an impact on the
yield of β-methyl-β-nitroamines (5e−5g).
To further highlight the applicability of this transformation, a
gram-scale experiment was conducted (Scheme 4). The
reaction proceeded effectively with 1a (8 mmol) in the
presence of 10 mol % [PdCl(allyl)]2 for 2 h, and 1.15 g of 4a
was obtained under the standard condition A.
In order to gain insight into how the β-methyl-β-nitroamines
5 were generated, several mechanistic experiments were carried
out (Scheme 5). According to previous experimental results, α-
Scheme 6. Proposed Mechanism
Scheme 4. Gram-Scale Experiment
C
DOI: 10.1021/acs.orglett.7b03631
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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with the aid of a Pd catalyst and the elimination of EtOH.7,8
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In summary, we have established a novel Pd-catalyzed three-
component amination and nitration reaction with simple and
readily available materials. Various important organic molecules
β-nitroamines were achieved through this transformation. In
addition, this strategy provides an elegant and efficient aza-
Henry reaction under mild conditions, and it may open up a
new viewpoint in the synthesis of β-nitroamines. Further
studies to investigate the synthetic applications of this reaction
are in progress.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03631.
■
S
Experimental procedures, condition screening table,
characterization data, and copies of NMR spectra for
all products (PDF)
(7) (a) Matsubara, Y.; Hirakawa, S.; Yamaguchi, Y.; Yoshida, Z.
Angew. Chem., Int. Ed. 2011, 50, 7670. (b) Olmos, A.; Sommer, J.; Pale,
P. Chem. - Eur. J. 2011, 17, 1907.
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Chung, B. Y.; Jia, Y. K. Org. Lett. 2006, 8, 195. (b) Jia, X.; Ren, Y.;
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: cewuwq@scut.edu.cn.
*E-mail: jianghf@scut.edu.cn.
ORCID
(9) (a) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org.
Lett. 2004, 6, 625. (b) Gomez-Bengoa, E.; Linden, A.; Lop
́
ez, R.;
Huanfeng Jiang: 0000-0002-4355-0294
Notes
Mugica-Mendiola, I.; Oiarbide, M.; Palomo, C. J. Am. Chem. Soc. 2008,
́
130, 7955. (c) Tan, C.; Liu, X.; Wang, L.; Wang, J.; Feng, X. Org. Lett.
2008, 10, 5305. (d) Hu, Y.; Zhou, Z.; Gong, L.; Meggers, E. Org.
Chem. Front. 2015, 2, 968.
The authors declare no competing financial interest.
(10) (a) Berestovitskaya, V. M.; Makarenko, S. V.; Bushmarinov, I. S.;
Lyssenko, K. A.; Smirnov, A. S.; Stukan’, A. E. V. Russ. Chem. Bull.
2009, 58, 1023. (b) Hao, F.; Asahara, H. A.; Nishiwaki, N. Org. Lett.
2017, 19, 5442.
ACKNOWLEDGMENTS
■
The authors thank the National Program on Key Research
Project (2016YFA0602900), the National Natural Science
Foundation of China (21420102003 and 21672072), and the
Fundamental Research Funds for the Central Universities
(2015ZY001 and 2017ZD062) for financial support.
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DOI: 10.1021/acs.orglett.7b03631
Org. Lett. XXXX, XXX, XXX−XXX