Electrochemical Dehydrogenative Imidation of N-Methyl-Substituted Benzylamines with Phthalimides for the Direct Synthesis of Phthalimide-Protected gem-Diamines

Article abstract of DOI:10.1021/acs.orglett.8b03624

A general and green electrochemical dehydrogenative method for the imidation of N-methyl benzylamines with phthalimides with excellent regioselectivities is reported for the first time. This operationally simple method offers a valuable tool to obtain str

Full text of DOI:10.1021/acs.orglett.8b03624

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Electrochemical Dehydrogenative Imidation of N‑Methyl-
Substituted Benzylamines with Phthalimides for the Direct
Synthesis of Phthalimide-Protected gem-Diamines
Fei Lian, Caocao Sun, Kun Xu, and Chengchu Zeng*
Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science & Bioengineering, Beijing University of
Technology, Beijing 100124, China
S
* Supporting Information
ABSTRACT: A general and green electrochemical dehydro-
genative method for the imidation of N-methyl benzylamines
with phthalimides with excellent regioselectivities is reported
for the first time. This operationally simple method offers a
valuable tool to obtain structurally diverse phthalimide-
protected gem-diamines.
hthalimide-protected gem-diamines are an important class
alkanes with phthalimide using di-tert-butyl peroxide as the
oxidant.5 The Meng and Jain groups realized the direct
imidation of C(sp3)−H bonds adjacent to a nitrogen atom
with phthalimide under KI/TBHP or CuBr/air oxidative
conditions, respectively.6,7 Although significant progress has
been made in the imidation of C(sp3)−H bonds,8 direct
imidation of N-methyl-substituted benzylamines with phthali-
mide is still unexplored. Considering the importance of
phthalimide-protected gem-diamines in medicinal chemistry,
and that there are many existing methods for the deprotection
of the benzyl group (Bn) in the resulting products for further
derivatization, the realization of a dehydrogenative imidation
of N-methyl substituted benzylamines with phthalimide for the
construction of N-Bn-N′-phthalimido gem-diamines is highly
desired.
P
of core structures of biologically active molecules (Scheme
1a).1 As such, there has been intensive efforts to identify
Scheme 1. Biologically Relevant Phthalimide-Protected
gem-Diamines and Imidation of C(sp3)−H Bonds with
Phthalimide
Organic electrosynthesis obviates the use of toxic chemical
oxidants or reductants and thus provides a green strategy for
organic synthesis.9 Recent studies have demonstrated the
power of organic electrosynthesis in dehydrogenative trans-
formations.10 In continuation of our interest in electrochemical
dehydrogenative reactions,11 we herein report the first example
of an electrochemical dehydrogenative imidation of N-methyl-
substituted benzylamines with phthalimide to afford phthali-
mide-protected gem-diamines with excellent regioselectivities
(Scheme 1c). In addition, an electrochemical dehydrogenative
amination of N-methyl-substituted benzylamines with azoles
under the same reaction conditions is also described.
We initiated our studies by using N,N-dimethylbenzylamine
1a and phthalimide 2a as model substrates, platinum net as the
anode, and a graphite plate as the cathode under constant
current conditions to identify the optimal reaction conditions
(Table 1). First, a series of electrolytes were examined, and the
results showed that Bu4NClO4 was the optimal supporting
electrolyte to give target product 3a in 67% yield, while other
convenient methods for phthalimide-protected gem-diamine
synthesis.2 In terms of synthetic efficiency and atom economy,
dehydrogenative imidation of C(sp3)−H bonds adjacent to a
nitrogen atom with phthalimide would be an attractive strategy
for the assembly of phthalimide-protected gem-diamines.3
However, compared with imidation of C(sp2)−H bonds,4
direct imidation of C(sp3)−H bonds with phthalimide is less
explored (Scheme 1b).5−7 In 2014, Hartwig and co-workers
established a robust copper-catalyzed imidation of unactivated
Received: November 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03624
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Condition
Scheme 2. Substrate Scope with Respect to N-Methyl-
a
Substituted Benzylamines
anode/
cathode
yield
b
entry
electrolyte
solvent
(%)
1
2
3
4
5
6
7
8
LiClO4
CH3CN
CH3CN
CH3CN
CH3CN
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/Ni
Pt/Fe
C/C
C/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
32
55
32
67
16
51
36
61
50
41
47
27
28
75
66
32
78
75
63
43
66
Bu4NPF6
Bu4NBF4
Bu4NClO4
Bu4NH2PO4 CH3CN
Et4NOTs
Et4NOAc
Et4NClO4
Et4NBF4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
MeOH
DCE
CH3CN/MeOH = 8:2
CH3CN/MeOH = 6:4
CH3CN/MeOH = 4:6
CH3CN/MeOH = 8:2
CH3CN/MeOH = 8:2
9
10
11
12
13
14
15
16
17
18
19
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
c
20
21
d
a
Reaction conditions: 1a (2.0 mmol), 2a (1.0 mmol), electrolyte (0.5
mmol), solvent (10 mL) as the mixed solvent, 40 °C, current density
b
c
of 5 mA/cm2, electrolyze in undivided cell for 5 h. Isolated yield. 1a
d
(1.0 mmol), 2a (2.0 mmol). Electrolyte (0.3 mmol).
commonly used electrolyte gave lower yields (entries 4 vs 1−3,
5−9). Further investigation of the electrode materials showed
that when platinum net was used as the cathode and anode, the
yield could be increased to 75% (entry 14). To improve the
chemical yield of 3a, a series of solvents were screened (entries
15−19). A satisfactory 78% yield of the desired product was
obtained when the ratio of CH3CN to MeOH by volume was
8:2 (entry 17), while other solvents such as MeOH or DCE
(entries 15−16), or other ratios of CH3CN to MeOH gave
lower yields (entries 18−19). Notably, when the substrate ratio
of 1a to 2a was inversed to 1:2, a lower yield (43%) of 3a was
obtained (entry 20). In addition, a 66% yield of product 3a was
isolated when the amount of the supporting electrolyte was
decreased to 0.3 equiv (entry 21).
Under the optimized reaction conditions, we began to
survey the scope and the generality of the protocol by
examining the reactions of a variety of N-methylbenzylamines
1 with phthalimide 2a. As shown in Scheme 2, the
corresponding products 3a−3u were obtained in up to 91%
yield. Generally, excellent yields were obtained for 1 having
electron-rich 4-aryl substituents (3b−3d). Substrates with
electron-deficient 4-aryl substituents reacted with lower yields
(3e−3j). The reaction of electron-deficient 4-nitrophenyl-
substituted 1k only gave the corresponding product 3k in 38%
yield. Altering the substituents to ortho or meta positions has
little influence on the yield (3l−3p). Moreover, disubstituted
substrates were also well tolerated under the conditions, giving
the corresponding products 3r−3t in up to 91% yield. Finally,
N-methyl-N-ethyl benzylamine 1u and N-benzyl-N-methyl-1-
a
Reaction conditions: 1 (2.0 mmol), 2a (1.0 mmol), Bu4NClO4 (0.5
mmol) in solvent of 8 mL of CH3CN and 2 mL of MeOH, current 10
mA, platinum net anode and platinum net cathode (working area: 2
cm2), undivided cell, 40 °C, 5 h, isolated yields.
phenylmethanamine 1v were examined, which delivered the
desired products 3u and 3v in 50% and 48% yields,
respectively. It is noteworthy that the reactions of 1u and 1v
showed regioselectivities, and the imidation of C(sp3)−H
bond of the methylene in ethyl and benzyl was not observed in
the reactions. We speculate that it may be due to steric factors.
Having established the substrate scope of N-methyl-
substituted benzylamines, the substrate scope of phthalimides
2 was then investigated, and the results are summarized in
Scheme 3. First, for the imidation of N,N-dimethylbenzylamine
1a, substituted phthalimides could also give the corresponding
products 3w−3x in excellent yields. When the phenyl moiety
in the phthalimide was replaced by pyridyl, the corresponding
product 3y was also obtained in 60% yield.
To make this methodology more appealing, the amination
reaction of N,N-dimethylbenzylamine 1a with azoles 4 was also
examined.12 When triazole was employed as the substrate, the
aminated products 5a/5a′ were obtained in 79% total yield
with a ratio of 1:13; while the aminated products 5b/5b′ were
obtained in 83% total yield with a ratio of 1:5 with
benzotriazole as the substrate.
Our protocol proved to be practical and easily scalable. As
shown in Scheme 4, when 20 mmol of N,N-dimethylbenzyl-
B
DOI: 10.1021/acs.orglett.8b03624
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Phthalimides and Azoles
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1a (2.0 mmol), 2 (1.0 mmol), Bu4NClO4 (0.5
mmol) in solvent of 8 mL of CH3CN and 2 mL of MeOH, current 10
mA, platinum net anode and platinum net cathode (working area: 2
cm2), undivided cell, 40 °C, 5 h, isolated yields.
Moreover, the electrochemical dehydrogenative amination of
N,N-dimethylbenzylamine with azoles was also realized.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03624.
amine 1a was treated with 10 mmol of phthalimide 2a under
standard conditions, a 53% yield of the desired adduct 3a was
obtained.
■
S
Scheme 4. Gram-Scale Experiment
Experimental details, conditional optimization, control
experiments, characterization data, NMR spectra, and
HRMS of all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zengcc@bjut.edu.cn.
ORCID
To gain more insight into the mechanism, cyclic
voltammetry (CV) experiments were carried out (see SI for
details). The results showed that substrate 1a has two
oxidation peaks at 0.8 and 1.0 V vs Ag/AgNO3 (0.1 M in
CH3CN), respectively, whereas no obvious oxidation wave was
observed for substrate 2a within the potential window
examined. In addition, the oxidation peak potential of
phthalimide potassium salt was observed at 1.1 V vs Ag/
AgNO3 (0.1 M in CH3CN). These results suggest that
substrate 1a is easier to be oxidized than substrate 2a. Notably,
the oxidation peak potential of the target product 3a was
observed at 1.1 V, higher than that of 1a, thereby avoiding the
overoxidation of 3a in the electrolysis process.
Based on the above experiments, a possible mechanism for
electrochemical dehydrogenative C−H imidation of N,N-
dimethylbenzylamine is described in Scheme 5. The reaction
sequence is initiated by anodic oxidation of N,N-dimethylben-
zylamine 1 to give radical cation 8, which undergoes
deprotonation and further oxidation to generate iminium
intermediate 9. Meanwhile, MeOH is reduced at the cathode
to give methoxide and H2.8 The formation of H2 could be
detected by GC (see SI for details). Phthalimide 2a is
deprotonated by methoxide to give intermediate 10, which
undergoes a Mannich-type addition to intermediate 9 to
generate product 3.
Chengchu Zeng: 0000-0002-5659-291X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Key
Technology R&D Program (2016YFD0400801) and the
National Natural Science Foundation of China (No.
21871019). Z.C.C. is thankful for financial support from the
Open Project Program of Beijing Key Laboratory of Flavor
Chemistry, Beijing Technology and Business University
(BTBU).
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Org. Lett. XXXX, XXX, XXX−XXX