Palladium-catalyzed oxidative amination of activated olefins with N-alkyl anilines for synthesis of tertiary (E)-enamines

Article abstract of DOI:10.1039/c4ra11543k

An efficient palladium-catalyzed oxidative amination of olefins with secondary anilines for the synthesis of tertiary (E)-enamines has been developed. Trimethylacetic acid (PivOH) played an important role in the reaction. This protocol tolerates a range o

Full text of DOI:10.1039/c4ra11543k

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Palladium-catalyzed oxidative amination of
activated olefins with N-alkyl anilines for synthesis
of tertiary (E)-enamines†
Cite this: RSC Adv., 2014, 4, 62042
Received 30th September 2014
Accepted 12th November 2014
*
Mi-Na Zhao, Xiao-Li Lian, Zhi-Hui Ren, Yao-Yu Wang and Zheng-Hui Guan
DOI: 10.1039/c4ra11543k
www.rsc.org/advances
An efficient palladium-catalyzed oxidative amination of olefins with the synthesis of enamines.14 Palladium-catalyzed oxidative
secondary anilines for the synthesis of tertiary (E)-enamines has been amination of olens with primary anilines for the synthesis of
developed. Trimethylacetic acid (PivOH) played an important role in enamines in the presence of LiBr have been reported by Jiang
the reaction. This protocol tolerates a range of functional groups and et al.15 However, these protocols are mainly focused on the
is a reliable method for direct synthesis of tertiary (E)-enamines in high synthesis of secondary (Z)-enamines. In connection with our
yields under mild conditions.
continuous interest in the N-alkyl anilines and enamines'
transformations,4,5 in this paper, we have developed an efficient
palladium-catalyzed oxidative amination of olens with
secondary anilines for the synthesis of a series of synthetic
useful tertiary (E)-enamines.5a
We commenced our study by investigating the palladium-
catalyzed oxidative amination of N-methyl aniline 1a with n-
butyl acrylate 2a (Table 1). The desired (E)-enamine 3aa was
Enamines and their derivatives are prevalent in numerous
natural products1 and have been widely applied in nucleophilic
addition reactions for synthesis of chiral compounds2 or aza-
heterocycles.3–5 Conventionally, enamines were synthesized by
condensation of aldehydes and ketones with amines, or Pd- or
Cu-catalyzed cross-coupling of vinyl halides with amines.6
However, these methods oen require rigorous conditions,
such as exclusion of moisture and air. Therefore, novel and
efficient methods for the direct synthesis of enamines have
been and continue to be an active area of research.7
Table 1 Optimization of reaction conditionsa
Oxidative amination reaction represents an attractive
strategy for the construction of C–N bonds.8 Particularly,
transition-metal-catalyzed oxidative amination of olens is an
important method to synthesize enamine derivatives. In recent
years, palladium-catalyzed oxidative amination of olens with
nonbasic amination reagents such as amides, sulfonamides or
imides, have been established for the synthesis of enamides.9
However, oxidative amination of olens with anilines still
remains challenging.10 The main issue of the reactions include:
(a) the competed hydroamination of olens occurred easily;11
(b) anilines could be oxidized to aromatic azo compounds;12 (c)
olens usually suffers from polymerization.13
Entry
Catalyst
Additive
Solvent
T (ꢀC)
Yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
—
KOAc
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
DCE
100
100
100
100
100
100
100
100
100
100
100
100
80
15
27
45
30
60
81
61
70
65
15
84
38
48
37
K2CO3
p-TsOH
HOAc
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
Recently, utilizing an ortho-substituent strategy, Obora and
co-workers have developed a palladium-catalyzed oxidative
amination of olens with ortho-substituted primary anilines for
9
THF
10
11
12
13
14
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
PdCl2(PPh3)2
PdCl2
PdCl2
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of
Education, Department of Chemistry & Materials Science, Northwest University, Xi'an
710127, P. R. China. E-mail: guanzhh@nwu.edu.cn
120
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [Pd] (5 mol%),
Cu(OAc)2 (1.2 equiv.), additives (1.0 equiv.) in solvent (2 mL) for 10 h
in air; isolated yields.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra11543k
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obtained in 15% yield in the presence of the Pd(OAc)2 catalyst with electron-donating groups, such as methyl, methoxyl, or
and 1.2 equiv. of Cu(OAc)2 in CH3CN at 100 ꢀC (Table 1, entry 1). electron-withdrawing groups, such as uoro, chloro, bromo,
To improve the reaction efficiency, various acids and bases were nitro, formyl and ester on the aryl rings all gave the corre-
screened as additives. Experiments suggest that the acid addi- sponding tertiary (E)-enamines 3aa–3qa in good to high yields,
tive plays an important role in the reaction (Table 1, entries 4– thus indicating that the electronic nature of the substrates has
6). The yield of (E)-enamine 3aa was dramatically improved to little inuence on the oxidative amination reaction. Ortho-
81% when PivOH was used as an additive (Table 1, entry 6). substituted anilines proceeded smoothly to give the corre-
Optimization of various palladium precursors and solvents sponding tertiary enamines 3ba, 3ea, 3ga and 3ja in high yields.
revealed that PdCl2 and CH3CN were suitable catalyst and These results revealed that the steric features of the 2-position
solvent respectively (Table 1, entry 11). Finally, the reaction of the anilines is indeed benecial to the oxidative amination
temperature was also varied, and 100 ꢀC gave the best result reaction, which is consistent with the results reported by
(Table 1, entries 13 and 14).
Obora.14 Expectedly, a- or b-naphthyl anilines were also toler-
With the optimized reaction conditions established, the ated to afford the corresponding enamines 3ra, 3sa in moderate
scope of the reaction was investigated (Table 2). This palladium- yields.
catalyzed oxidative amination reaction displayed good func-
In addition, anilines with different alkyl substituent group
tional group tolerance and proved to be a general method for on the nitrogen atom, such as ethyl substituted aniline show
facile construction of tertiary (E)-enamines. N-Methyl anilines good reactivity, producing the corresponding enamine 3ta in
72% yield. Notably, cyclic substrate, such as tetrahydroquino-
line 1u, was also tolerated in the reaction to give the desired (E)-
butyl 4-(3,4-dihydroquinolin-1-(2H)-yl)but-2-enoate 3ua in 55%
Table
2 Palladium-catalyzed oxidative amination of olefins with
yield. However, aliphatic secondary amines, such as diethyl-
amine and piperidine were less reactive and gave only trace
amounts of the desired enamines.
various N-alkyl anilinesa
Next, various acrylates 2 were investigated to extend the
substrate scope (Table 3). Acrylates, such as 2b–2e, showed good
reactivity in the reaction to give the desired products 3ab–3ae in
60–84% yields (Table 3, entries 1–4). However, the (E)-3-(methyl-
(phenyl)amino)acrylonitrile 3ag was obtained in only 8% yield
(Table 3, entry 6). And no reaction occurred when acrylamide 2f,
ethyl 2-methylacylate 2h and 1-phenylprop-2-en-1-one 2i were
used as the substrates (Table 3, entries 5, 7–8).
To demonstrate the synthetic utility of this reaction, a gram
scale (10 mmol, 1.07 g) reaction was performed under the
standard conditions. The desired (E)-enamine 3aa was obtained
in 75% yield (Scheme 1).
To gain more insight into the mechanism of the reaction, the
hydroamination product methyl 3-(methyl(phenyl)amino)prop-
anoate 4 was conducted under the standard conditions
(Scheme 2). No 3ab product was observed implying that the
hydroamination/oxidation pathway is less likely.
On the basis of the aforementioned results and previous
reports,9,14–16 a tentative mechanism for the reaction is proposed
in Scheme 3. The reaction was initiated by the coordination of
the olen 2 to Pd(II) to give a palladium-olen complex A, which
undergoes nucleophilic attack by N-methyl aniline 1 to generate
a s-alkylpalladium complex B. We assumed that PivOH plays a
role in the protonation of N-methyl aniline to prevent the
competing coordination of N-methyl aniline with Pd(II),4a thus,
promoting the coordination of acrylate 2 with Pd(II). Subse-
quently, b-hydride elimination of the intermediate B affords the
(E)-enamine 3 and Pd(0) species. Finally, the Pd(0) species was
reoxidized by Cu(OAc)2 to regenerate the active Pd(II) catalyst.
In summary, we have developed an efficient palladium-
catalyzed oxidative amination of olens with secondary
anilines for the synthesis of tertiary (E)-enamines. PivOH plays
an important role in this transformation. This protocol tolerates
a range of functional groups and is a reliable method for the
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), PdCl2 (5 mol%),
Cu(OAc)2 (1.2 equiv.), PivOH (1.0 equiv.) in CH3CN (2 mL) for 6–12 h
at 100 ꢀC in air; isolated yields.
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Table 3 Palladium-catalyzed oxidative amination of various olefins
with N-methyl anilinea
Entry
1
Substrate
Product
Yield (%)
75
Scheme 3 Tentative mechanism for palladium-catalyzed oxidative
amination of olefins with secondary anilines.
2
3
4
76
60
84
rapid elaboration of readily available secondary anilines into a
variety of tertiary (E)-enamines in high yields. Further study on
the reaction scope is in progress.
Acknowledgements
This work was supported by generous grants from the
National Natural Science Foundation of China (21272183,
21002077), and the Fund of the Rising Stars of Shanxi Province
(2012KJXX-26).
5
0
Notes and references
6
7
8
0
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