Electrosynthesis of enaminones directly from methyl ketones and amines with nitromethane as a carbon source

Article abstract of DOI:10.1039/c5cc02730f

An efficient and mechanistically different method for the electrosynthesis of enaminone directly from methyl ketones, amines and nitromethane was developed. This transition-metal-free method proceeded at room temperature to give a wide array of enaminones

Full text of DOI:10.1039/c5cc02730f

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DOI: 10.1039/C5CC02730F
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Electrosynthesis of enaminones directly from methyl ketones and
amines with nitromethane as a carbon source
Kun Xu, a,b Zhenlei Zhang,a Peng Qian, a Zhenggen Zha a* and Zhiyong Wang a*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient and mechanistically different method for the electrosynthesis Our laboratory has a longstanding interest in C-H functionalization
of enaminone directly from methyl ketones, amines and nitromethane was under electrochemical conditions,[8,9] which motivated us to initiate
developed. This transition-metal-free method proceeded at room the study on developing a new electrochemical route toward the
temperature to give a wide array of enaminones in one step, utilizing synthesis of enaminone. Retrosynthetic analysis showed that
nitromethane as the carbon source.
construction of enaminone units directly from methyl ketones,
amines, and suitable carbon sources would be more appreciable,
since it eliminates prefunctionalization steps required for substrate
activation (Scheme 2). Herein, we report an efficient and
mechanistically different method to synthesize enaminones directly
from readily available materials through a convient electrochemical
process.
Enaminones exist widely in both natural products and synthetic
compounds of high utility in pharmaceutical chemistry. [1] The wide
synthetic utility along with the synthetic challenge presented by this
structural feature have inspired the development of many efficient
methods to enable their chemical synthesis.[2-5] However, most of
these protocols suffered from the limited availability of starting
materials, limited substitution pattern and high reaction
temperature. Recently, Ueno, Kuwano and coworkers developed a
useful Ni-catalyzed oxidative amination reaction to synthesize
enaminone (Scheme 1, eq (1)).[6] More recently, Zhang and
coworkers reported an elegant method to construct enaminone
catalyzed by CuI with acetylide ion as a synthon (Scheme 1, eq
(2)).[7] Although considerable progress has been made in
enaminone synthesis, the development of a metal-free strategy to
give direct access to various enaminones under mild conditions is
highly desired.
O
O
NHR1R2
C
+
+
Ar
NR1R2
Ar
Scheme 2. Retrosynthetic analysis of enaminone.
Initial optimization attempts focused on the survey of suitable
carbon source under electrochemical conditions (see Table S1 in the
Supporting Information for details). When nitromethane was
employed as the carbon source, the corresponding enaminone 3aa
was obtained in 41% yield; while other carbon sources failed to
deliver meaningful yields of the product under the same reaction
conditions. These results encouraged us to investigate the reaction
conditions further (Table 1). Initial experiments were performed to
investigate the solvent effect of the reaction. The best yield was
obtained by using MeOH as the solvent; however, no products were
formed when other commonly used solvents were employed
(entries 3-7). Further studies showed that KI was the best
electrolyte (entry 8) and iodide ion was essential for the
transformation (entries 8, 9 vs 10-12). To further improve the yield,
some additives were tested. When 2, 2, 2-Trifluoroethanol (TFE)
was employed as the additive, the yield increased to 69% (entry
13); when water (5 equiv) was added to the reaction, the yield
decreased to 58% (entry 14). Increasing the current to 40 mA led to
the decrease of the chemical yield (entry 15). Further assessment of
the reaction conditions indicated that an oxygen atmosphere had a
positive effect on the reaction; however, a nitrogen atmosphere led
to a lower yield (entry 16).
Ueno and Kuwano's work
O
O
R1
Ni(cod)2/Me3P
R1
HN
R2
+
(1)
(2)
Ph
N
R2
Ph
100 o
C
Zhang's work
O
O
R1
CuI
85 o
R1
+
CaC2
+
HN
R2
Ph
H
Ph
N
R2
C
Scheme 1. Representative methods for the synthesis of enaminone.
a.Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory
of Soft Matter Chemistry and Department of Chemistry Collaborative
&
Innovation Center of Suzhou Nano Science and Technology, University of Science
and Technology of China, Hefei, Anhui, 230026, P. R. China. Fax:(+)86-551-
63603185; E-mail: zwang3@ustc.edu.cn.
b.College of Chemistry and Pharmaceutical Engineering, Nanyang Normal
University, Nanyang, Henan, 473061 P. R. China.
†
Electronic
DOI: 10.1039/x0xx00000x
Supplementary
Information
(ESI)
available.
See
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Table 1. Optimization of the reaction conditions.[a]
Entry[a]
Solvent
EtOH
Electrolyte
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-Bu4NI
KI
Yield[b]
1
2
41
55
0
MeOH
DMSO
CH2Cl2
CH3CN
DMF
3
4
0
5
0
6
0
7
MeNO2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
0
8
63
59
trace
9
NaI
10
11
12
13c
14d
15c,e
16c,f
n-Bu4NBr
LiClO4
NaBr
[
a] Reaction condition: 1 (0.5 mmol), 2a (2 mmol), KI (1 mmol), CF3CH2OH (1
0
trace
69
mmol), MeOH (8 mL), CH3NO2 (1 mL), platinum sheet as an anode and a cathode
in an undivided cell, at a constant current of 20 mA for 7 hours, room temperature.
To further establish the general utility of this transformation, the
substrate scope for other amines were then examined. As
presented in Table 3, a series of aliphatic amines were good
reaction partners with acetophenone and nitromethane, and the
corresponding enaminones 3ab-3af were obtained in moderate to
good yields. For the linear amines, the bulky amine led to a
decrease of the yield due to the steric effect (3ad-3ae vs 3ab-3ac).
For the cyclic amine with a functional group, the reaction also went
smoothly to give the corresponding product 3af in 56% yield.
Importantly, the challenging substrate dimethyl amine (33wt% in
water) worked effectively in this reaction system to deliver the
product 3ab in 74 % yield.
KI
KI
58
KI
53
KI
37
[a] Reaction condition: 1a (0.5 mmol), 2a (2 mmol), electrolyte (1 mmol), solvent
(8 mL), CH3NO2 (1 mL), platinum sheet as an anode and a cathode in an
undivided cell, at a constant current of 20 mA for 7 hours, room temperature. [b]
Isolated yield. [c] Added 2 equiv of CF3CH2OH. [d] Added 5 equiv of H2O. [e]
The current was 40 mA. [f] N2 was used instead of O2.
With the optimized conditions in hand, the substrate scope of the
reaction was investigated by evaluating a variety of aromatic
methyl ketones. As shown in Table 2, the reaction proceeded
smoothly with different substrates to afford enaminones in
moderate to good yields. The electronic properties of aromatic
methyl ketones were found to greatly influence the reaction. In
general, the weak electron-donating (Me, 3ba) and electron-
withdrawing (F, Cl, Br, 3ea-3ga) groups has little effect on the yield;
however, the strong electron-donating (OMe, 3ca, 3na) and
moderate electron-withdrawing (CF3, 3ia) groups led to the
decrease of the chemical yields. For nitro-substituted
acetophenone, the reaction didn’t proceed at all. On the other
hand, the steric effect of substituent on the phenyl group had some
influence on the reaction. The para- and meta-substituents had
little effect on the yield, however, ortho-substituents led to slightly
lower yields (3ja vs 3ba, 3ka vs 3ea).
Table 3. Substrate scope of amines.[a]
[a] Reaction condition: 1a (0.5 mmol), 2 (2 mmol), KI (1 mmol), CF3CH2OH (1
mmol), MeOH (8 mL), CH3NO2 (1 mL), platinum sheet as an anode and a cathode
in an undivided cell, at a constant current of 20 mA for 7 hours, room temperature.
Table 2. Substrate scope of methyl ketones.[a]
To gain insight into the reaction mechanism, a series of control
experiments were performed (Scheme 3). When phenacyl iodine 5
was employed as the coupling partner with piperidine 2a and
nitromethane under the standard conditions, the corresponding
enaminone 3aa was obtained in 63% yield, which suggested that
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phenacyl iodine 5 was likely to be the intermediate of this reaction
[Eq. (1)]. As phenacyl iodine 5 was a possible intermediate of this
reaction, tertiary amine 6 could be formed easily in the presence of
excess amine 2a. When tertiary amine 6 was employed as the
starting material, enaminone 3aa was obtained in 71% yield, which
indicated that tertiary amine 6 was likely to be the intermediate of
this tandem reaction [Eq. (2)]. When another tertiary amine 7 was
employed as the starting material, enaminone 3aa was found to be
the main product; however, only trace amount of enaminone 3ag
was detected by GC-MS [Eq. (3)]. This result indicated that the
tertiary amine may undergo a subsequent C-N cleavage step to lead
the final product formation. When nitroalkene 11 was treated with
piperidine in MeOH at room temperature, enaminone 3aa was
obtained in 79% yield in less than 5 minutes, which revealed that
this tandem reaction may proceed via an addition/elimination
sequence involving nitroalkene 11 as an intermediate [Eq. (4)].
Scheme 4. A plausible mechanism for this reaction.
In summary, we developed an efficient electrochemical method
for the synthesis of enaminone directly from readily available
starting materials at room temperature. This method not only
provided a metal-free route for the synthesis of enaminones but
also represented a new strategy for using nitromethane as a
capable carbon source. We are currently investigating extensions of
this chemistry to other reactions as well as the mechanism
responsible for the observed chemistry.
Acknowledgements
Financial support from the Natural Science Foundation of China
(2127222, 91213303, 21172205, 21432009, J1030412, 21472177) is
greatly acknowledged.
Notes and references
Scheme 3. Control experiments.
1
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plausible mechanism for this reaction was described in Scheme 4.
Initially, phenacyl radical 4[10] is generated from acetophenone 1a
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liberation of one molecule of HI. Radical coupling[12] between 4 and
iodide radical yields phenacyl iodine 5. Subsequent nucleophilic
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6，which undergoes anodic oxidation to yield intermediate 8. At
2
3
4
•−
the same time, superoxide anion radical O2 is generated by
electrochemical reduction of O2.[13] Then proton and electron
•−
transfer from 8 to O2 yields iminium ion 9.[14] An addition of
nitromethane to 9 leads to the formation of adduct 10, which is
followed by an elimination step to give nitroalkene 11. Finally, 1, 4-
addition of piperidine to nitroalkene 11 affords intermediate 12,
which subsequently undergoes a β-H elimination to generate the
final product 3aa with complete E-selectivity. [15]
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