Electrochemical Oxidative C(sp3)?H/N?H Cross-Coupling for N-Mannich Bases with Hydrogen Evolution

Article abstract of DOI:10.1002/cssc.201802676

N-Mannich bases are an important structure in various functional molecules. A new protocol to synthesize N-Mannich bases was established through electrochemical external-oxidant-free C(sp³)?H/N?H cross-coupling with hydrogen evolution. Various

Full text of DOI:10.1002/cssc.201802676

Accepted Article
Title: Electrochemical Oxidative C(sp3)–H/N-H cross-coupling for N-
Mannich Bases with Hydrogen Evolution
Authors: Pan Wang, Zhenlin Yang, Ting Wu, Chenyang Xu, Ziwei
Wang, and Aiwen Lei
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Electrochemical Oxidative C(sp3)–H/N-H cross-coupling for N-
Mannich Bases with Hydrogen Evolution
Pan Wang, [a] Zhenlin Yang, [a] Ting Wu, [a] Chenyang Xu, [a] Ziwei Wang[a] and Aiwen Lei*[a]
Abstract: N-Mannich bases are a kind of important structure in
various functional molecules. A novel protocol to synthesize N-
Mannich bases has been established through electrochemical
external oxidant-free cross C(sp3)-H/N-H coupling with hydrogen
evolution. Various N-methylanilines have been explored in this
transformation. Besides, simple amides, heteroatom-containing
amides and succinimides were well tolerant in moderate to good
yields. In addition, the electrochemical dehydrogenative C(sp3)-H/N-
H cross coupling could be scale up in 5 mmol. Using triethyl phosphite
as trapping agent, phosphorylation product was detected. At the same
time, KIE experiments showed that the cleavage of C-H bond is the
rate-limiting step.
construct C(sp3)-X bond.[9] Herein, we would like to communicate
our recent progress on anodic oxidative cross C(sp3)-H/N-H
coupling to synthesize N-Mannich bases with hydrogen evolution
(Scheme 2, 3).
Nitrogen-containing molecules are of great importance in
organic synthesis and exhibit excellent biological activity and
medicinal activity.[1] For example, N-Mannich bases have shown
pharmacologically potent in antibiotic and inhibitor (Scheme 1).[2]
At present, multicomponent Mannich reaction is still the most
classic method to deliver N-Mannich bases via C-N bond
formation (Scheme 2, 1).[3] However, this classic reaction usually
requires using formaldehyde as C1 linker or prefunctionalization
of amide. In the past decades, many efforts have been paid to
form C(sp2)-N bond.[4] Direct C(sp3)-N bond formation though
oxidative C−H/N−H cross-coupling remains challenges due to the
great difficulties in activating C(sp3)-H bond.[5] Although some
pioneer works have been developed in direct C(sp3)-H amidation
under transition-metal catalysis and metal-free conditions
(Scheme 2, 2),[6] some limitations still exist in these
transformations, such as the use of transition metal or excess
external oxidants, harsh reaction conditions, poor toleration of
substituents and so on. Therefore, it is urgent to develop a new
strategy to synthesize N-Mannich bases through oxidative cross
C-H/N-H coupling.
Scheme 1. Representative significant N-Mannich Bases.
Scheme 2. Methods for synthesizing N-Mannich Bases.
As a green and efficient strategy in organic synthesis, anodic
electrochemistry has gained more and more attentions.[7]
Electrochemical anodic oxidation can provide a powerful and
highly selective means for building new chemical bonds. Recently,
great progress has been made in electrochemical intramolecular
and intermolecular cross C(sp2)-H/N-H coupling.[8] Direct C(sp3)-
H functionalization through electrochemical anodic oxidation
might be challenging but an environmentally friendly way to
We started our study by employing N,N,4-trimethylaniline (1a)
and phthalimide (2a) as model substrates to optimize the reaction
conditions. When using the co-solvent of acetonitrile and acetic
acid, the C(sp3)-H/N-H cross-coupling product (3aa) could be
delivered in 82% yield under 10 mA constant current for 3 h (Table
1, entry 1). Under standard conditions, hydrogen gas could be
detected by GC analysis. The acid plays a key role in this
electrochemical transformation. No desired product could be
obtained in the absence of acetic acid (Table 1, entry 2). When
we replaced acetic acid with other alkyl carboxylic acid, the
reactions were carried out in lower efficiency (Table 1, entry 3-4).
No desired product was observed when inorganic and organic
strong acids were added to the reaction (Table 1, entry 5-6). Then
we investigated the effect of solvent, MeOH, DMF and DMSO
could not promote this transformation and poor yields were
detected (Table 1, entry 7-9). Due to the high price of platinum
plate, other cheap cathodic materials were examined in this
electrochemical C(sp3)-N bond formation reaction. To our delight,
[a]
P. Wang, Z Yang, T. Wu, C. Xu, Z. Wang and A. Lei*
Institute for Advanced Studies (IAS), College of Chemistry and
Molecular Sciences, Wuhan University, Wuhan 430072, Hubei, P.
R. China
Homepage: http://aiwenlei.whu.edu.cn/lawsys/
E-mail: aiwenlei@whu.edu.cn
Prof. A. Lei
National Research Center for Carbohydrate Synthesis, Jiangxi
Normal University, Nanchang 330022, P. R. China
Supporting information for this article is given via a link at the end of
the document
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using nickel plate as cathode, a slightly decreased yield was
obtained (Table 1, entry 10). Both iron plate cathode and carbon
cloth showed less reactivity with platinum plate cathode (Table 1,
entry 11-12). Keeping constant electric quantity, lower reaction
yields were obtained either by decreasing or increasing the
operating current (Table 1, entry 13-14). No desired product could
be obtained without electricity (Table 1, entry 15).
Unfortunately, only traces of C(sp3)-H/N-H cross-coupling
product could be detected when N-methylaniline reacted with
phthalimide. By-product of azobenzene and aniline could be
detected.
Table 2. Electrochemical Oxidative C(sp3)–H Amidation with different N-
methylanilines.[a]
Table 1. Optimization of the reaction conditions. [a]
Entries
Variation from the standard conditions
Yield (%) [b]
1
none
82
2
without AcOH (9 mL CH3CN)
HCOOH instead of AcOH
nPrCOOH instead of AcOH
H2SO4 instead of AcOH
TsOH·H2O instead of AcOH
MeOH instead of CH3CN
DMF instead of CH3CN
DMSO instead of CH3CN
Ni plate cathode
n.d.
trace
74
3
4
5
n.d.
n.d.
33
6c
7
8
27
9
36
10
11
12
13
14
15
73
Fe plate cathode
19
.
C cloth cathode
24
[a] Standard conditions: graphite rod anode (ф 6 mm), Pt plate cathode (15
mm×15 mm×0.3 mm), constant current = 10 mA, 1 (1.0 mmol), 2 (0.50 mmol),
nBu4NBF4 (1.0 mmol), CH3CN/AcOH (8.0/1.0 mL), 60 °C, 3 h, undivided cell (2.2
F).
7 mA, 4.3 h
31
15 mA, 2 h
53
no electricity
n.d.
Table 3. Electrochemical Oxidative C(sp3)–H Amidation with different amides.[a]
[a] Standard conditions: graphite rod anode (ф 6 mm), Pt plate cathode
(15 mm×15 mm×0.3 mm), constant current = 10 mA, 1a (1.0 mmol), 2a
(0.50 mmol), nBu4NBF4 (1.0 mmol), CH3CN/AcOH (8.0/1.0 mL), 60 °C, 3 h,
undivided cell (2.2 F). [b] Isolated yield, [c] 1 mmol TsOH·H2O was added,
n.d. = not detected.
To illustrate the synthetic utility of this electrochemical
protocol, the efforts were paid to explore scope of this electro-
oxidative C(sp3)-H/N-H cross-coupling. First, different N-
methylaniline derivative were applied in this transformation
(Table 2). Simple N,N-dimethylaniline would selectively
generate C(sp3)-H/N-H cross-coupling product in this
electrochemical reaction (3ba). Halide substituents including
F, Cl and Br were well tolerated to furnish corresponding
desired products in high yields (3ca-3ea). N,N-
dimethylanilines bearing electron with-drawing substituents
such as acetyl group, eater group, trifluoromethyl group and
cyano group gave decreased reaction yields (3fa-3ia). Strong
electron donating substituents such as tertiary butyl, phenyl
and methoxyl were also suitable for this electrochemical
[a] Standard conditions: graphite rod anode (ф 6 mm), Pt plate cathode (15
mm×15 mm×0.3 mm), constant current = 10 mA, 1 (1.0 mmol), 2 (0.50 mmol),
nBu4NBF4 (1.00 mmol), CH3CN/AcOH (8.0/1.0 mL), 60 °C, 3 h, undivided cell
(2.2 F). [b] 20 mol% Cp2Fe was added.
protocol
(3ja-3la).
Furthermore,
N,4-dimethyl-N-(p-
tolyl)aniline furnished the corresponding desired product in
moderate yield (3ma). Other dialkylated anilines such as N,N-
diethyl-4-methylaniline and 1-phenylpiperidine were also
applied to examine the reactivity, but fewer desired products
were obtained due to the cleavage of C-N bond.
Oxidative C(sp3)-H amidation using 1a was investigated for a
range of amides (Table 3). Phthalimide bearing halide substituent
was well tolerated in this transformation, furnishing corresponding
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desired product in moderate yield (3ab). Beside phthalimide,
simple cyclic amides were also suitable for this transformation.
When azetidin-2-one was applied in the mixture, the
corresponding C(cp3)-H/N-H cross-coupling product could be
afforded in quantitative yield (3ac). Utilizing ferrocene as additive,
cyclic amides without other heteroatom such as pyrrolidin-2-one,
2-piperidone and ɛ-caprolactam could also be tolerated in this
electrochemical amidation reaction, providing the corresponding
products in 50% to 79% yields (3ad-3af). Heteroatom-containing
amide such as 3-morpholinone, oxazolidin-2-one and thiazolidin-
2-one were highly facile to afford the desired products (3ag-3ai)
in moderate to good yields ranging from 59% to 83%. In addition,
succinimide was also found to be suitable substrate and afforded
the product in moderate yield.
intermolecular competitive reaction of 1a and [D6]-1a and KIE
value of kH/kD = 3.88 (Scheme 4, b). When reaction was carried
out with [D3]-1a as substrate, the ratio of C(sp3)-H bond
amidation products [D3]-3ac and [D2]-3ac is 5.06:1 (Scheme 4, c).
These experiment results indicated that the cleavage of C-H bond
is rate-limiting step.
To further evaluate the effect of acetic acid, we carried out
cyclic voltammetry experiment (Figure 1). The oxidation peak of
1a in acetonitrile was obtained at 0.92 V. After 1 mL acetic acid
was added to the reaction mixture, the oxidation peak of 1a
decreased to 0.84 V, which might indicate that acetic acid could
promote the oxidation of 1a at anode. At the same time, CVs of
2a have also been carried out at different scan rate and no
obvious oxidation peaks were detected whether in acetic acid
solution or not. The oxidation peak of 3aa in the mixture of
acetonitrile and acetic acid was also obtained at 1.1 V.
0
Scheme 3. Gram scale synthesis.
Blank
-4
1a
1a+AcOH
2a
2a+AcOH
3aa+AcOH
-8
The scalability of electrochemical external oxidant-free
dehydrogenative C(sp3)-H amidation was evaluated in a 5.0
mmol scale (Scheme 3). With the same ratio of electric current
applied, moderate yield of 3aa was obtained, which highlights the
potential of this electrochemical hydrogen-evolution reaction in
future applications.
-12
-16
0.0
0.5
1.0
1.5
2.0
Protential (V vs Ag/AgCl)
Figure 1. Cyclic voltammetry of 1a, 2a and 3aa in CH3CN (9 mL) or
CH3CN/AcOH (8/1 mL) with nBu4NBF4 (0.2 mmol) under nitrogen at a platinum-
disk electrode at a scan rate of v=0.1 V/s.
Scheme 4. Mechanistic studies.
Next, efforts were paid to investigating the reaction
mechanism. First, trapping experiment was conducted to explore
the existence of intermediates (Scheme 4, a). When 5 equiv of
triethyl phosphite was added in the reaction under the standard
conditions, no desired C(sp3)-N bond formation product could be
detected while a C(sp3)-H phosphorylation product 4aa was
obtained in 58% yield. This result suggested the radical or imine
cation pathway might involve in the reaction.[10] Then kinetic
isotope effect experiments were carried out. First, we did an
Scheme 5. Proposed mechanism.
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Base on the above experiment results and literature reports,
a possible mechanism was proposed in the Scheme 5. First,
single-electron-transfer (SET) oxidation of N,N,4-trimethylaniline
by anode could furnish the corresponding radical cation. Tertiary
α-amino carbon radical will be delivered after the deprotonation of
the radical cation. The radical will undergo the second SET
oxidation to generate the imine cation which was attacked by
phthalimide subsequently. Final deprotonation of the cation
intermediate will lead to the formation of the desired C(sp3)-N
bond-formation product. At the same time, hydrogen gas is
produced by cathode through reduction of acetic acid.
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external oxidant-free dehydrogenative C(sp3)-H/N-H cross-
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Further application of this electrochemical dehydrogenative
cross-coupling and detailed mechanism research are underway
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Experimental Section
General procedure for the electro-oxidative C(sp3)-H/N-H cross-
coupling: In an oven-dried undivided three-necked flask (25 mL) equipped
with a stir bar, aniline (0.50 mmol), amide (1.0 mmol), nBu4NBF4 (329 mg,
1.0 mmol) and CH3CN/AcOH (8/1 mL) were combined and added. The
bottle was equipped with graphite electrode as the anode and platinum
electrodes (1.5×1.5×0.3 cm3) as the cathode and was then charged with
nitrogen. The reaction mixture was stirred and electrolyzed at a constant
current of 10 mA under 60 °C for 3 h. When the reaction was finished, the
solution was extracted with EtOAc (3×10 mL) and H2O (3×10 mL). The
combined organic layer was dried with Na2SO4, filtered. The solvent was
removed with a rotary evaporator. The pure product was obtained by flash
chromatography on silica gel using petroleum ether and ethyl acetate as
the eluent (50:1).
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21390402, 21520102003) and the Hubei
Province Natural Science Foundation of China (2017CFA010).
The Program of Introducing Talents of Discipline to Universities of
China (111 Program) is also appreciated.
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Keywords: Electrochemistry • C(sp3)-N formation • Hydrogen
evolution• radical • C-H functionalization
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P. Wang, Z. Yang, T. Wu, C. Xu, Z.
Wang, A. Lei*
Page No. – Page No.
Electrochemical Oxidative C(sp3)–
H/N-H cross-coupling for N-Mannich
Bases with Hydrogen Evolution
Electro-oxidative C(sp3)–H/N-H cross-coupling with Hydrogen Evolution: A
novel protocol to synthesize N-Mannich bases has been established through
electrochemical external oxidant-free cross C(sp3)-H/N-H coupling with hydrogen
evolution. Various N-methylanilines have been explored in this transformation.
Besides, simple amides, heteroatom-containing amides and succinimides were well
tolerant in moderate to good yields.
This article is protected by copyright. All rights reserved.