Electrochemically Oxidative α-C-H Functionalization of Ketones: A Cascade Synthesis of α-Amino Ketones Mediated by NH4I

Article abstract of DOI:10.1021/acs.joc.6b01595

An efficient electrochemical protocol for the synthesis of α-amino ketones via the oxidative cross-dehydrogenative coupling of ketones and secondary amines has been developed. The electrochemistry performs in a simple undivided cell using NH₄I

Full text of DOI:10.1021/acs.joc.6b01595

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Article
Electrochemically Oxidative alpha-C-H Functionalization of Ketones#
A Cascade Synthesis of alpha-Amino Ketones mediated by NH4I
Sen Liang, Cheng-Chu Zeng, Hong-Yu Tian, Bao-Guo Sun, Xu-Gang Luo, and Fa-Zheng Ren
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01595 • Publication Date (Web): 04 Nov 2016
Downloaded from http://pubs.acs.org on November 4, 2016
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Electrochemically Oxidative αꢀCꢀH Functionalization of Ketones：A Cascade Synthesis of
αꢀAmino Ketones Mediated by NH4I
Sen Liang,a,b ChengꢀChu Zeng,a,c,* HongꢀYu Tian,a BaoꢀGuo Sun,a,* XuꢀGang Luo,b Faꢀzheng Renb
a
Beijing advanced innovation center for food nutrition and human health, School of Food and
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Chemical Engineering, Beijing Technology and Business University, Beijing 100048, China
b Beijing advanced innovation center for food nutrition and human health, College of Food Science
& Nutritional Engineering, China Agricultural University, Beijing 100083, China
c
College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124,
China
Corresponding author: zengcc@bjut.edu.cn; sunbg@btbu.edu.cn
Keywords: CꢀH oxidative functionalization, indirect electrolysis, αꢀamino ketone, halide ion as
redox catalyst
Abstract:
An efficient electrochemical protocol for the synthesis of αꢀamino ketones via the oxidative
cross dehydrogenative coupling of ketones and secondary amines has been developed. The
electrochemistry performs in a simple undivided cell using NH4I as a redox catalyst and cheap
graphite plate as electrodes under constant current conditions. Gram scale reaction demonstrates the
practicality of the protocol. The reaction is proposed to procced through an initial αꢀiodination of
ketone, followed by a nucleophilic substitution of amines.
Graphical Abstract:
1. Introduction
Direct oxidative cross dehydrogenative coupling of C−H and N−H bond to form a new C−N
bond has emerged as an important method in organic synthesis. It represents a high stepꢀ and
atomꢀeconomical process since prefunctionalization of the substrates is avoided and hydrogen is the
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only formal byproduct.1 Along this line, significant advances have been made, especially in the
oxidative C(sp2)–H couplings to form various C–N bonds.2 Extensive efforts have also been
devoted to the oxidative amination of C(sp3)–H bond, such as relatively active benzylicꢀ,3
allylicꢀC–H,4 as well as αꢀCꢀH of alkyl ethers 5.
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Figure 1. Some examples of biologically significant αꢀamino ketones
αꢀC(sp3)–H functionalization and amination of ketones are also significant chemical
conversions since αꢀamino ketones constitute the core structural scaffold of various natural products
and pharmaceuticals. For example, bupropion, pyrovalerone and amfepramone are proved to be
potential pharmacotherapies for antidepressant and psychoactive diseases (Figure 1).6 Moreover,
αꢀamino ketones are important intermediates and precursors for the synthesis of heterocycles and
1,2ꢀamino alcohols.7 Consequently, atomꢀeconomical and efficient approaches for the synthesis of
αꢀamino ketones are in demand.
Typically, αꢀamino ketones are prepared by the substitution reaction of αꢀhalo/hydroxy ketones
with nucleophilic nitrogen sources8 or αꢀamination of carbonyl compounds with electrophilic
nitrogen sources.9 These procedures require prefunctionalization of starting substrates. The direct
oxidative amination of αꢀC(sp3)−H bonds of carbonyl compounds provides an alternative approach
for the construction of highly functionalized αꢀamino ketones.10 For instance, MacMillan and
coꢀworkers developed a procedure for the αꢀamination of ketones, esters, and aldehydes via a
combination of copper catalysts and bidentate nitrogen ligands.10e Transition metalꢀfree oxidative
αꢀC−H amination of ketones was also described by Guo and coꢀworkers using ammonium iodide as
a catalyst and sodium percarbonate as a coꢀoxidant.10f Very recently, an oneꢀpot strategy to
synthesize αꢀamino ketones has also been developed by Sekar and coꢀworkers starting from
benzylic secondary alcohol using Nꢀbromosuccinimide (NBS) as an oxidant via sequential alcohol
oxidation, αꢀbromination of ketone and CꢀN bond formation.6b Although much progress has been
made in the processes described above, the need to use toxic and stoichiometric or excess of
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external oxidant does not meet the guiding principles of green and sustainable chemistry (Scheme
1).11
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Electrochemistry has proved to be an environmentally benign method to achieve the formation
of a new chemical bond and a functional group conversion by using electron as oxidant rather than
additional chemicals.12 In this context, we have explored novel redox catalysts based upon the
triarylimidazole scaffold for the oxidative functionalization of CꢀH bonds.13aꢀb Recently, we have
also applied simple halide ions as redox catalysts to achieve electrochemical CꢀH bond
functionalization, leading to the formation of new CꢀC, CꢀN, CꢀO and CꢀS bonds.13cꢀf Based on our
experience in halide ionsꢀmediated indirect electrolysis, we hypothesized that a constant current
electrolysis (CCE) of ketone in the presence of halide ion might initially generate αꢀhalocarbonyl
ketone that would further undergo a substitution reaction in the presence of a nucleophilic amine
source to fulfill the desired αꢀamino ketones (Scheme 1).
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Scheme 1. Methods for the synthesis of αꢀamino ketones
Herein, we reported an electrochemical protocol for the one pot synthesis of αꢀamino ketones
using NH4I as a redox catalyst. The protocol features the following advantages: (1) the chemistry is
performed via an αꢀiodination and amination sequence, which avoids the preꢀpreparation and
isolation of the key intermediate, αꢀiodo ketone, thus minimizing the production of waste; (2) the
anode serves as a coꢀoxidant that is physically separated from the organic layer containing the
substrate and is thus easily removed; therefore, no terminal chemical coꢀoxidant is needed; and (3)
the process is conveniently carried out at a constant current in a simple beakerꢀtype cell. To the best
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of our knowledge, this work represents the first example of the electrochemically oxidative αꢀCꢀH
amination of ketones and further demonstrates that halide ions are versatile mediators capable of
promoting a variety of different transformations.
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2. Results and discussion
To demonstrate the feasibility of the one pot electrochemical αꢀamination of ketones via the
αꢀiodination and amination sequence, we commenced on the optimization studies using
propiophenone (1a) and piperidine (2a) as model substrates. Based on our previous successful use
of a graphite working electrode in halide ionꢀinduced CꢀH bond functionalization,13 we chose to use
it rather than to explore other options. The initial constant current electrolysis of a mixture of 1a (1
mmol) and 2a (3 mmol) was carried out in LiClO4 / CH3CN at room temperature in the presence of
0.5 equiv of NaI as a redox catalyst. To our delight, the desired product 3a was obtained in 61%
yield (entry 1, Table 1). When NaI was replaced by other halide salt, such as NaCl, NaBr, NH4Br or
nꢀBu4NBr, product 3a was not detected (entries 2ꢀ5), indicating that chloride and bromide are
inefficient for the cross dehydrogenative coupling reaction. Further catalysts screening disclosed
that NH4I provided the best yields of 3a, although KI and Bu4NI also led to acceptable results
(entries 6ꢀ8). Notably, in the absence of NH4I, 3a was not produced (entry 9), thereby revealing that
iodide ion plays an essential role for the cross dehydrogenative coupling reaction. The assay of the
amount of NH4I disclosed that 0.5 equiv of NH4I was necessary in order to obtain acceptable yield.
Lowering the loading to 0.2, 0.3 or 0.4 equiv. or increasing to 0.7 equiv. resulted in an decrease of
the yield of 3a to 0%, 56%, 69%, 73% respectively (entries 10ꢀ13). We observed that the yield of 3a
improved from 43% to 59% when the ratio of 1a to 2a was increased from 1:1.5 to 1:2 (entries
14ꢀ15). A further increase in the ratio to 3 equiv of 2a afforded the highest yield of 3a (entry 8).
Additional increases did not improve the efficiency (entry 16).
The effect of current density on the reaction was also examined. The reaction did not proceed
without electrolysis (entry 17), indicating the necessity of electrolysis. It was found that almost
identical yield of 3a was produced when a current density of 6 mA/cm2 (entry 18) or 10 mA/cm2
(entry 19) was employed instead of an optimal 8 mA/cm2.
We further investigated the possibility to produce αꢀamino ketones electrochemically, but in
the absence of the supporting electrolyte, LiClO4. It was observed that the voltage of the cell was in
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the range of 2.0 – 3.0 volts in the presence of 0.1 M LiClO4, whereas it increased to 4.0 – 5.0 volts
when conductive salt was not added as a result of the diminished conductivity. Nevertheless, the
reaction proceeded smoothly without sacrificing efficiency, and nearly the same yield of adduct 3a
was obtained (entry 20). In addition, rising temperature has no significant impact on the yield of
product 3a (entry 21).
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In order to investigate the possible effects of solvent, several solvents were examined. As
shown in Table 1, when the reaction was performed in CH3OH, the wellꢀknown ketalization
reaction occurred and 2ꢀhydroxylꢀ1,1ꢀdimethoxypropylbenzene was obtained (entry 22).14 When
DMF and DMSO were used as solvents (entries 23ꢀ24), the voltage increased sharply and resulted
in a dramatic corrosion of the working electrode. Moreover, the desired product 3a was not detected
at all. Based upon these observations, we suggested that MeCN was the best solvent for the
reaction.
From the results described above, we concluded that the optimal reaction conditions call for
constant current electrolysis using 0.5 equiv of NH4I as the redox catalyst and CH3CN as the
solvent in an undivided cell equipped with a graphite plate anode and a graphite cathode.
Table 1. Optimization of the reaction conditions a
Entry
2a (equiv)
Redox cat. (equiv) J/(mA/cm2) Solvent Yield b
1
2
3
4
5
3
3
3
3
3
NaI (0.5)
NaCl (0.5)
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8
8
8
8
MeCN
MeCN
MeCN
MeCN
MeCN
61
0
NaBr (0.5)
0
NH4Br (0.5)
nꢀBu4NBr (0.5)
0
0
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KI (0.5)
nꢀBu4NI (0.5)
NH4I (0.5)
NH4I (0)
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ꢀ
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
DMF
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65
72
0
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3
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3
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20c
21d
22e
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3
NH4I (0.2)
NH4I (0.3)
NH4I (0.4)
NH4I (0.7)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
0
3
56
69
73
43
59
70
0
3
3
1.5
2
4
3
3
6
10
8
8
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8
73
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0
3
3
3
3
3
0
3
DMSO
0
a
Reaction conditions: propiophenone 1a (1 mmol), piperidine 2a and 0.1 M LiClO4 as supporting
electrolyte in 20 mL of solvent, undivided cell, graphite plate anode and cathode, room temperature,
CCE.
b 1H NMR yields using 1,3,5ꢀtrimethoxybenzene as an internal standard.
c Additional supporting electrolyte LiClO4 was not employed.
d T = 50 oC
e NaOH (1 equiv.) was added.
With the optimized conditions in hand, we turned toward exploration of the scope and
limitation of the αꢀamination reaction of ketones under the standard conditions (Table 2). First, the
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reactions of propiophenone 1a with various secondary amines were investigated. It was observed
that the reaction of 1a and cyclic secondary amines, such as 4ꢀmethylpiperidine (2b),
3ꢀmethylpiperidine (2c), morpholine (2e), and 1,2,3,4ꢀtetrahydroisoquinoline (2f) proceeded
smoothly and afforded the corresponding αꢀamination products 3b, 3c, 3e and 3f in 30−65%
isolated yield. However, 2ꢀmethylpiperidine (2d) was not a suitable coupling partner owing to the
steric hindrance, its reaction with propiophenone 1a did not give the corresponding adduct 3d.
Acyclic secondary amines also reacted with propiophenone 1a, albeit in a bit lower yield. For
example, Nꢀmethylbenzylamine (2g) and Nꢀethylbenzylamine (2h) afforded the corresponding
αꢀamination products 3g and 3h in 28% and 32% yield. Notably, aliphatic and aryl primary amine
did not work. For example, when butylamine (2i), cyclohexanamine (2j) and
pꢀmethylbenzeneamine (2k) were used as the amine sources, the corresponding adducts 3iꢀ3k were
not obtained.
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The oxidative cross dehydrogenative coupling of various propiophenones with piperidine were
also examined. It was observed that electronꢀpoor and –rich propiophenone proceeded smoothly
with piperidine. More specifically, the direct amination reaction was most efficient when an
electronꢀwithdrawing substituent was appended on the benzene ring of propiophenone. For example,
the chloroꢀ and fluoroꢀsubstituted propiophenones, 1b and 1d, afforded the corresponding adducts
3l and 3p in 70% and 75% yields, respectively, higher than that of 3a (65% yield). On the contrary,
when electronꢀdonating group, such as methylꢀ and methoxyl was installed in the phenyl ring, the
corresponding 3q and 3s was isolated in a slightly lower yield. This observation indicates that the
electrochemical αꢀamination of ketone prefers a substrate that is prone to enolate formation. Indeed,
when aliphatic ketone, such as 1h, was subjected to reaction with piperidine under the standard
electrochemical conditions, the corresponding dehydrogenative coupling product 3t did not
generate, due to the less prone to enol/enolate formation of aliphatic ketone. Moreover,
αꢀsubstituted propiophenones were also not suitable partners. For example, when αꢀmethyl
propiophenone (1i) and cyclopropylphenylmethanone (1j) were subjected to electrochemical
coupling with piperidine, the starting ketones remained intact and the corresponding adduct 3u and
3v were not obtained due to the steric hindrance. Notably, it was observed that the αꢀamination of
2ꢀcyclopropylꢀ1ꢀphenylethanone, 1k, proceeded smoothly and the corresponding 3w was obtained
in 45% yield. The observation implies that radical intermediate 5k might not be generated and
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therefore rule out the possibility of being a radical pathway for the electrochemical αꢀamination of
ketones (Detailed discussion see mechanism section and Scheme 5). In addition, the electronꢀrich
aromatic system do not undergo FriedelꢀCrafts iodination under these electrochemical conditions.
Table 2. Substrate scopes of αꢀamino ketones synthesis a
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Entry
Ketone 1
Amine 2
2a, R=H
Product 3
Yield (%) b
O
O
1a, R1=H
N
3a
3b
3c
3d
65
60
R
R
1
2
3
4
HN
1
R
2b, R=4ꢀMe
2c, R=3ꢀMe
2d, R=2ꢀMe
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trace
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N
HN
O
5
30
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3e
O
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50
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3f
NH
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O
R
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3g
3h
NH
R
O
NH
NH
2
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12
13
14
0
trace
0
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2j
3i
3j
3k
3l
O
H N
2
HN
O
H
N
H2N
2k
2a
1b, R1=4ꢀCl
O
N
HN
HN
70
Cl
O
O
O
N
N
O
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16
48
44
2d
2g
3m
3n
Cl
Cl
NH
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O
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21
1c, R1=3ꢀCl
1d, R1=4ꢀF
N
60
75
52
55
50
2a
3o
3p
3q
3r
3s
HN
R1
1e, R1=4ꢀMe
1f, R1=3ꢀMe
1g, R1=4ꢀMeO
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O
O
N
22
23
24
25
a
Pr
0
0
1h
1i
3t
3u
3v
3w
Bu
Bu
Pr
O
O
O
N
O
O
N
0
1j
O
N
45
1k
Reaction conditions: ketone (1 mmol), amine (3 mmol), NH4I (0.5 mmol) and 0.1 M LiClO4 as
supporting electrolyte in 20 mL of MeCN, undivided cell, graphite plate anode, graphite plate
cathode, room temperature, CCE, 14 F/mol.
b The isolated yield after column chromatography.
To further demonstrate the practicability of this oneꢀpot protocol, a gramꢀscale reaction was
also explored using 8 mmol of 1a (1.07 g) under the standard reaction conditions. This
transformation proceeded smoothly and 3a was isolated in a 55% yield without significant loss of
reaction efficiency (Scheme 2).
Scheme 2. Gramꢀscale electrochemically oxidative αꢀCꢀH amination of propiophenone (1a) with
piperidine (2a).
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In order to better understand the reaction mechanism and to determine the possible active
intermediates involved, several control experiments were conducted. As shown in Scheme 3, when
molecular iodine was employed as oxidant, the desired product was obtained in a 50% yield
(Scheme 3, a). Therefore, the in situ generated molecular iodine (I2) was suggested to be one of the
active species. Moreover, the reaction of 2ꢀiodoꢀ1ꢀphenylpropanꢀ1ꢀone, 4a,10e and piperidine gave
excellent yield of 3a (Scheme 3, b), which suggests that 4a is a possible intermediate in this
transformation and that a nucleophilic substitution might be involved in the reaction process.
In principle, the reaction of 1a with electrophilic nitrogen source, such as Nꢀiodopiperidine
may also lead to product 3a. To verify this, Nꢀiodopiperidine 5 was synthesized separately and
subjected to reaction with 1a. The results prove that the desired product 3a was not detected,
therefore the pathway involving the participation of an electrophilic nitrogen source was ruled out
(Scheme 3, c).
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O
O
I2 (1 equiv)
a)
b)
c)
MeCN, 50 oC
N
N
H
1a (1 mmol)
3a
3a
2a (3 mmol)
50% a
O
O
MeCN, 30 oC
N
I
N
H
2a
(3 mmol)
4a
(1 mmol)
O
90% a
O
MeCN, 30 oC
N
N
I
3a
1a
(1 mmol)
5
(3 mmol)
trace
a 1H NMR yields using 1,3,5ꢀtrimethoxybenzene as an internal standard
Scheme 3. Control experiments
To further gain insight into the mechanism of the electrochemically oxidative αꢀCꢀH amination
of ketones with amines, the electrochemical reaction of 1a and 2a was repeated while monitoring in
real time by GC and GCꢀMS. As shown in Figure 2, with the proceeding of electrolysis, two new
peaks with retention times at 17.27 min and 19.67 min appeared while the intensity of piperidine
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(the peak at 6.64 min) and propiophenone (the peak at 12.79 min) decreased (spectra 1ꢀ3, Figure 2).
By GCꢀMS (EI) analysis and comparison with authentic samples of 4a and 3a, we can assign that
the peaks at 17.27 min and 19.67 are 2ꢀiodopropiophenone, 4a, and product 3a, respectively.
Moreover, it was observed that 2ꢀiodopropiophenone disappear quickly, if the current power supply
was turn off while stirring at room temperature. Based on these results, it is safe to believe that 4a is
an intermediate and, once it forms, soon undergoes nucleophilic substitution with amine 2a to give
the final product 3a.
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Figure 2. Propiophenone 1a (1 mmol), Piperidine 2a (3 mmol) and 0.1 M LiClO4 as supporting
electrolyte in 20 mL of solvent, undivided cell, graphite plate anode and cathode, 30 oC, CCE.
It is worth noting that oxidative αꢀamination of aryl ketone may also involve a radical pathway.
For example, Guo and coworkers reported αꢀC−H amination of ketones using ammonium iodide as
the catalyst and sodium percarbonate as the coꢀoxidant.10e The authors proposed that the in situ
generated molecular iodine decompose into iodine radical, which abstracts the αꢀH of
propiophenone to form a carbonꢀcentered radical intermediate A. Followed by a single electron
transfer (oxidation), the radical intermediate A converts to cation B. Finally, the nucleophilic
substitution of amine to B gives the desired αꢀamination products (Scheme 4). Similar radical
mechanism was also proposed by Batra et al for the αꢀnitrotion of ketones using I2 as catalyst and
H2O2 as coꢀoxidant in DMSO.15
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Scheme 4. A radical pathway for the αꢀamination of aryl ketone proposed by Guo et al
To clarify whether our electrochemical αꢀamination of ketone involves the formation of radical
intermediate A, a radical clock experiment was performed. As mentioned in Table 2, when substrate
1k was subjected to electrolysis in the presence of 2a under the standard electrochemical conditions,
adduct 3w was obtained in acceptable yield. Since we did not find the presence of
5ꢀiodoꢀ1ꢀphenylꢀ2ꢀpentenꢀ1ꢀone,
1ꢀphenylpentaꢀ2,4ꢀdienone
or
5ꢀpiperidinꢀ1ꢀphenylꢀ
1
2ꢀpentenꢀ1ꢀone from the crude reaction mixture using H NMR methode, and therefore the radical
pathway, similar to that reported by Guo,10e is ruled out.
Scheme 5. Radical clock experiment.
It is necessary to mention that, when TEMPO and BHT were added as a radical scavenger, the
αꢀamination reaction of ketone did not work. This was observed for both the electrochemical
reaction as well as the control experiment with molecular iodine. However, the outcomes do not
represent a proof of a radical process since it is reported that molecular iodine could oxidize
TEMPO,16 with high possibility through an innerꢀsphere electron transfer.17
On the basis of the observations described above, we propose a mechanism for the
electrochemical αꢀamination of ketone with secondary amine. As illustrated in Scheme 6, the
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reaction begins with the anodic oxidation of iodide to generate molecular iodine, which undergoes
reaction with ketone 1 to form αꢀiodo ketone 4, along with one molecule of HI. Once the key
intermediate 4 is formed, it soon undergoes a nucleophilic substitution reaction with amine, leading
to the final αꢀamination product 3, accompanying the second molecular HI. Simultaneously, the in
situ generated HI is reduced to evolve H2 on the surface of cathode. In the course of the reaction,
iodide ion is regenerated from steps of the αꢀiodination of ketone 1 to 4 and nucleophilic
substitution of 4 to 3, and reꢀenters the redox catalyst cycle, thereby only subꢀstoichiometric or
catalytic amount of NH4I is required.
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Scheme 6. The proposed reaction mechanism for the formation of α‑amino ketones.
3. Conclusion
In conclusion, we have developed an efficient electrochemical protocol for the synthesis of
αꢀamino ketones via the oxidative cross dehydrogenative coupling of ketones and secondary amines
at ambient temperature. The electrochemistry was performed under constant current conditions in a
simple undivided cell using NH4I as the redox catalyst and cheap graphite plate as working
electrode. A wide range of functional groups are proved to be compatible with the standard
conditions. Gram scale reaction of 1a and 2a demonstrates the practicality of the protocol. In
addition, it is possible to carry out the chemistry without having to employ additional supporting
electrolyte. Mechanistic studies reveal that the electrochemical αꢀCꢀH amination of ketones likely
undergoes initial αꢀiodination of ketone, followed by a nucleophilic substitution of amines. In this
way, the iodide ion can be used catalytically, thereby avoiding the utilization of stoichiometrical
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amount of molecular iodine or a combination of iodide and coꢀoxidant and therefore represents an
environmentally benign means by which to achieve the transformation. Application of these ideas
and results to other types of reactions is underway in our laboratory.
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4. Experimental
4.1. Instruments and reagents
All melting points were measured with an electrothermal melting point apparatus and are
uncorrected. NMR spectra were recorded with a 300 MHz spectrometer (300 MHz 1H frequency, 75
MHz 13C frequency). Chemical shifts are given as δ values (internal standard: TMS). Coupling
constants are reported in Hz. Starting materials and solvents were obtained from commercial
sources and used without further purification. Products were purified by chromatography on silica
gel (Petroleum ether/EtOAc). GC analysis was performed using gas chromatograph and gas
chromatograph–mass spectrometer. The column used was a HPꢀ5 and HPꢀ5MS capillary column
(30 m, 0.25 mm i.d., and 0.25 mm film) and the gas carrier was N2 and He at a rate of 1 ml/min.
o
o
The injector, detector and MS transfer line temperature were maintained at 250 C, 250 C and 230
oC. For the HPꢀ5 and HPꢀ5MS column, the oven temperature was held at 50 oC for 1 min, raised to
o
o
250 C at 10 C/min and held for 4 min. An electron ionization system was used with ionization
energy of 70 eV.
4.2 Procedure for the synthesis of 2ꢀcyclopropylꢀ1ꢀphenylꢀ1ꢀethanone (1k)
4.2.1 Procedure for the synthesis of 1ꢀphenylbutꢀ3ꢀenꢀ1ꢀol 18
To a 250 mL threeꢀnecked flask was equipped with a magnetic stirrer, a pressure equalizing
dropping funnel, and reflux condenser mounted with a nitrogen source. To the flask were added
magnesium (1.2 g, 50 mmol), a small amount of iodine, and 10 mL of ether. To this was added a
small amount allyl chloride. The reaction mixture was stirred until the purple iodine color
disappeared at room temperature. To this was added 20 mL of a solution of allyl chloride (3.8 g, 50
mmol) slowly at −10 °C. After 30 min, a solution of benzaldehyde (5.3 g, 50 mmol) in 30 mL of
ether was added dropwise at such a rate to maintain the internal temperature below −10 °C. After 2
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h, the reaction was quenched with a 0.1 M aqueous solution of HCl, followed by the addition of 40
mL ether. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, and
removed under reduced pressure. The crude product was purified by silicaꢀgel column
chromatography. 1ꢀphenylbutꢀ3ꢀenꢀ1ꢀol was obtained as a colorless oil (5.9 g, 80% yield).
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1ꢀPhenylbutꢀ3ꢀenꢀ1ꢀol: H NMR (300 MHz, CDCl3): δ 2.46 (br, 1H), 2.50 (m, 2H), 4.69 (m,
1H), 5.10ꢀ5.17 (m, 2H), 5.72ꢀ5.85 (m, 1H), 7.23ꢀ7.34 (m, 5H). 13CNMR (75 MHz, CDCl3): δ 43.7,
73.2, 118.3, 125.8, 127.5, 128.3, 134.4, 143.8.
4.2.2 Procedure for the synthesis of 1ꢀphenylbutꢀ3ꢀenꢀ1ꢀone 19, 20
To a 200 mL round bottom flask containing a stirbar was added the above obtained
1ꢀPhenylbutꢀ3ꢀenꢀ1ꢀol (5.9 g, 40 mmol). To the flask were added 10 mL of acetone. To this was
o
added a solution of Jones' reagent (25 mL) and H2O (25 mL) at 0 C. The mixture was stirred at 0
oC for 2 h, H2O (50 mL) was added, and extracted with Et2O. The combined organic layers were
washed with brine, dried with anhydrous magnesium sulfate and removed under reduced pressure.
The crude product was purified by silicaꢀgel column chromatography. 1ꢀphenylbutꢀ3ꢀenꢀ1ꢀone was
obtained as a colorless oil (4.9 g, 85% yield).
1
1ꢀPhenylbutꢀ3ꢀenꢀ1ꢀone: H NMR (300 MHz, CDCl3): δ 3.75 (dt, J = 6.6 Hz, J = 1.2 Hz, 2H),
13
5.19ꢀ5.25 (m, 2H), 6.03ꢀ6.16 (m, 1H), 7.44ꢀ7.59 (m, 3H), 7.95ꢀ7.96 (m, 2H); CNMR (75 MHz,
CDCl3): δ 43.4, 118.7, 128.3, 128.6, 131.0, 133.2, 136.5, 198.0.
4.2.3 Procedure for the synthesis of 2ꢀCyclopropylꢀ1ꢀphenylꢀ1ꢀethanone 21, 22
To a 250 mL round bottom flask containing a stirbar was added Et2Zn (30 mmol, 1.5 M in
o
hexanes) and dry CH2Cl2 (20 mL) under N2. The solution was cooled to 0 C, and a solution of
trifluoroacetic acid (3.42 g, 30 mmol) in CH2Cl2 (10 mL) was added dropwise into the reaction
mixture by syringe. After stirring for 20 min, a solution of CH2I2 (8.0 g, 30 mmol) in CH2Cl2 (10
mL) was added. After an additional 20 minutes of stirring, a solution of the 1ꢀPhenylbutꢀ3ꢀenꢀ1ꢀone
(4.4 g, 30 mmol) in CH2C12 (10 mL) was added, and the reaction mixture was slowly warmed to
room temperature. After an additional 1 h of stirring, the reaction mixture was quenched with a 0.1
M aqueous solution of HCl and extracted with Et2O. The combined organic layers were washed
with brine, dried with anhydrous magnesium sulfate and removed under reduced pressure. The
crude
product
was
purified
by
silicaꢀgel
column
chromatography.
2ꢀCyclopropylꢀ1ꢀphenylꢀ1ꢀethanone was obtained as a colorless oil (3.8 g, 80% yield).
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2ꢀCyclopropylꢀ1ꢀphenylꢀ1ꢀethanone: H NMR (300 MHz, CDCl3): δ 0.17ꢀ0.21 (m, 2 H),
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0.43ꢀ0.63 (m, 2 H), 1.12ꢀ1.21 (m, 1 H), 2.88 (d, J = 6.6 Hz, 2 H), 7.43ꢀ7.48 (m, 2 H), 7.53ꢀ7.58 (m,
13
1 H), 7.91ꢀ7.99 (m, 2 H). C NMR (75MHz, CDCl3): δ 4.5, 6.6, 43.8, 128.1, 128.5, 132.9, 136.9,
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200.0
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4.3 General procedure for the electrochemically oxidative αꢀCꢀH amination of ketones
A 50 mL undivided cell was equipped with a graphite plate cathode and a graphite plate anode
(each about 2 × 3 cm2 and the distance is about 0.5 cm) which were connected to a DC regulated
power supply. To the cell was added ketone 1 (1 mmol), amine 2 (3 mmol), NH4I (0.5 mmol) and
LiClO4 (0.1 M) dissolved in 20 mL of CH3CN. The mixture was electrolyzed under constant current
conditions at 8 mA/cm2 at room temperature while stirring. The electrolysis was terminated when
14 F/mol of charge had been consumed. After the electrolysis, the solvent was removed under
reduced pressure. The residue was poured into a saturated aqueous Na2S2O3 and the product was
then extracted with DCM (3×10 mL), dried over MgSO4, and concentrated in vacuum. The residue
was purified by column chromatography on silica gel using a mixture of petroleum ether/EtOAc as
eluent.
2ꢀPiperidinꢀ1ꢀphenylpropanꢀ1ꢀone (3a)10e Yield: 141 mg, 65 %; Brown oil; Flash chromatography
1
(petroleum ether/ethyl acetate, 1/1); H NMR (CDCl3, 300 MHz): δ 1.24 (d, J = 6.9 Hz, 3H),
1.37ꢀ1.42 (m, 2H), 1.51ꢀ1.56 (m, 4H), 2.48ꢀ2.58 (m, 4H), 4.06 (q, J = 6.6 Hz, 1H), 7.40ꢀ7.45 (m,
13
2H), 7.50ꢀ7.56 (m, 1H), 8.09ꢀ8.12 (m, 2H); C NMR (CDCl3, 75 MHz) δ 11.1, 24.3, 26.3, 50.7,
65.0, 128.2, 128.8, 132.7, 136.4, 201.1.
2ꢀ(4ꢀMethyl)piperidinꢀ1ꢀphenylꢀpropanꢀ1ꢀone (3b)10e Yield: 139 mg, 60 %; Brown oil; Flash
1
chromatography (petroleum ether/ethyl acetate, 5/1); H NMR (CDCl3, 300 MHz): δ 0.81 (d, J =
6.0 Hz, 3H), 1.04ꢀ1.26 (m, 6H), 1.52ꢀ1.62 (m, 2H), 2.11 (td, J = 11.4 Hz, 2.4 Hz, 1H), 2.37 (td, J =
11.4 Hz, 2.4 Hz, 1H), 2.73 (d, J = 11.1 Hz, 1H), 2.89 (d, J = 11.1 Hz, 1H), 4.07 (q, J = 6.6 Hz, 1H),
13
7.43 (t, J = 7.5 Hz, 2H), 7.53 (t, J = 7.5 Hz, 1H), 8.09 (d, J = 7.5 Hz, 2H); C NMR (CDCl3, 75
MHz): δ 11.3, 21.9, 30.8, 34.4, 34.8, 48.5, 51.7, 64.9, 128.2, 128.9, 132.7, 136.5, 201.1.
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2ꢀ(3ꢀMethyl)piperidinꢀ1ꢀyl)ꢀ1ꢀphenylpropanꢀ1ꢀone (3c) Yield: 150 mg, 65 %; Brown oil; Flash
chromatography (petroleum ether/ethyl acetate, 5/1); 1H NMR(CDCl3, 300 MHz): δ 0.81 (q, J = 6.0
Hz, 3 H), 1.04ꢀ1.26(m, 6 H), 1.52ꢀ1.62(m, 2 H), 2.11(td, J = 11.4、2.4 Hz, 1 H), 2.37(td, J = 11.4、
2.4 Hz, 1 H), 2.73(d, J = 11.1 Hz, 1 H), 2.89(d, J = 11.1 Hz, 1H), 4.07(q, J = 6.6 Hz, 1 H), 7.43(t, J
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= 7.5 Hz, 2 H), 7.53(t, J = 7.5 Hz, 1 H), 8.09(d, J = 7.5 Hz, 2 H); C NMR(CDCl3, 75 MHz): δ
10.6, 10.8, 19.6, 25.6, 25.9, 31.2, 31.6, 32.9, 48.7, 51.7, 56.4, 59.4, 64.9, 128.2, 128.9, 128.9, 132.7,
136.5, 136.5, 200.9, 201.0. HRMS (ESI) m/z calcd for C15H22NO(M+H) 232.1696, found 232.1691.
2ꢀMorpholinoꢀ1ꢀphenylpropanꢀ1ꢀone (3e)10e Yield: 66 mg, 30 %; Brown oil; Flash
chromatography (petroleum ether/ethyl acetate, 3/1); 1H NMR(CDCl3, 300 MHz): δ 1.28 (d, J = 6.9
Hz, 3H), 2.51ꢀ2.65 (m, 4H), 3.63ꢀ3.75 (m, 4H), 4.06 (q, J = 6.9 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H),
13
7.55 (t, J = 7.2 Hz, 1H), 8.07 (d, J = 7.2 Hz, 2H); C NMR (CDCl3, 75 MHz): δ 11.7, 50.0, 64.7,
67.1, 128.4, 128.7, 133.0, 136.0, 200.2;
2ꢀ(3,4ꢀDihydroisoquinolinꢀ2(1H)ꢀyl)ꢀ1ꢀphenylpropanꢀ1ꢀone (3f)10e Yield: 133 mg, 50 %; Brown
oil; Flash chromatography (petroleum ether/ethylacetate, 10/1); 1H NMR (CDCl3, 300 MHz): δ 1.38
(d, J = 6.9 Hz, 3H), 2.80ꢀ2.87 (m, 4H), 3.80 (d, J = 14.7 Hz, 1H), 3.92 (d, J = 14.7 Hz, 1H), 4.31 (q,
J = 6.6 Hz, 1H), 7.00ꢀ7.13 (m, 4 H), 7.42ꢀ7.46 (t, J = 7.5 Hz, 2H), 7.52ꢀ7.56 (t, J = 7.2 Hz, 1H),
13
8.14−8.16 (d, J = 7.2 Hz, 2H); C NMR(CDCl3, 75 MHz): δ 11.2, 29.5, 47.1, 52.0, 64.1, 125.5,
125.9, 126.5, 128.3, 128.6, 128.9, 132.9, 134.4, 134.7, 136.1, 200.5.
2ꢀ(NꢀBenzylꢀNꢀmethylamino)ꢀ1ꢀphenylpropanꢀ1ꢀone (3g)10e Yield: 71 mg, 28 %; Brown oil;
Flash chromatography (petroleum ether/ethylacetate, 10/1); 1H NMR (CDCl3, 300 MHz): δ 1.31 (d,
J = 6.6 Hz, 3H), 2.21 (s, 3H), 3.63 (s, 2 H), 4.31 (q, J = 6.6 Hz, 1H), 7.19ꢀ7.29 (m, 5 H), 7.43 (t, J =
7.2 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.98 (d, J = 7.2 Hz, 2H); 13C NMR (CDCl3, 75 MHz): δ 8.8,
37.6, 58.3, 62.1, 127.0, 128.2, 128.2, 128.9, 128.9, 132.7, 136.4, 139.0, 200.8.
2ꢀ(NꢀBenzylꢀNꢀethylamino)ꢀ1ꢀphenylpropanꢀ1ꢀone (3h)10e Yield: 85 mg, 32 %; Brown oil; Flash
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chromatography (petroleum ether/ethyl acetate, 10/1); H NMR(CDCl3, 300 MHz): δ 1.02 (t, J =
7.2 Hz, 3H), 1.28 (d, J = 6.6 Hz, 3H), 2.56 (q, J = 7.2 Hz, 2 H), 3.53 (d, J = 13.8 Hz, 1H), 3.70 (d, J
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= 13.8 Hz, 1H), 4.40 (q, J = 6.6 Hz, 1H), 7.15ꢀ7.17 (m, 5H), 7.38ꢀ7.42 (t, J = 7.5 Hz, 2H), 7.50ꢀ7.54
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(t, J = 7.5 Hz, 1H), 7.90ꢀ7.92 (d, J = 7.5 Hz, 2H); C NMR(CDCl3, 75 MHz): δ 8.8, 13.7, 44.3,
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54.6, 58.8, 126.9, 128.1, 128.1, 128.9, 128.9, 132.5, 136.8, 139.8, 201.9.
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2ꢀPiperidinꢀ1ꢀ(4ꢀchlorophenyl)propanꢀ1ꢀone (3l)6b Yield: 203 mg, 70 %; Brown oil; Flash
chromatography (petroleum ether/ethylacetate, 8/1); 1H NMR (CDCl3, 300 MHz): δ 1.22 (d, J = 6.6
Hz, 3H), 1.36ꢀ1.42 (m, 2H), 1.47ꢀ1.55 (m, 4H), 2.42ꢀ2.53 (m, 4H), 3.96 (q, J = 6.6 Hz 1H), 7.39 (d,
J = 8.7 Hz, 2H), 8.08 (d, J = 8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 10.2, 24.3, 26.3, 50.6, 65.5,
128.4, 130.5, 134.6, 138.9, 199.7.
2ꢀMorpholinoꢀ1ꢀ(4ꢀchlorophenyl)propanꢀ1ꢀone (3m)10e Yield: 122 mg, 48 %; Brown solid; mp:
83ꢀ87℃; Flash chromatography(petroleum ether/ethyl acetate, 3/1); 1H NMR (CDCl3, 300 MHz): δ
1.25 (d, J = 6.6 Hz, 3H), 2.47ꢀ2.61 (m, 4 H), 3.59ꢀ3.70 (m, 4H), 3.97 (q, J = 6.6 Hz, 1H), 7.39 (d, J
= 8.7 Hz, 2H), 8.07 (d, J = 8.7 Hz, 2H); 13C NMR(CDCl3, 75 MHz): δ 10.9, 49.8, 65.1, 67.0, 128.6,
130.3, 134.2,139.3 198.8.
2ꢀ(NꢀMethylꢀNꢀphenylmethylꢀamino]ꢀ1ꢀ(4ꢀchlorophenyl)propanꢀ1ꢀone (3n) Yield: 126 mg,
44 %; Brown oil; Flash chromatography (petroleum ether/ethylacetate, 10/1); 1H NMR (CDCl3, 300
MHz): δ 1.29 (d, J = 6.6 Hz, 3H), 2.20 (s, 3H), 3.62 (s, 2H), 4.22 (q, J = 6.6 Hz, 1H), 7.19ꢀ7.30 (m,
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5H), 7.40 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 7.5 Hz, 2H); C NMR(CDCl3, 75 MHz): δ 8.05, 37.5,
58.4, 62.1, 127.2, 128.3, 128.5, 128.9 130.5, 134.6, 138.8, 139.0, 199.4. HRMS (ESI) m/z calcd for
C17H19ClNO(M+H)+ 288.1150, found 288.1153.
2ꢀPiperidinꢀ1ꢀ[(3ꢀ(chlorophenyl)]propanꢀ1ꢀone (3o)23 Yield: 151 mg, 50 %; Brown oil; Flash
chromatography(petroleum ether/ethyl acetate, 8/1);1H NMR (300 MHz, CDCl3): δ 1.23 (d, J = 6.9
Hz, 3H), 1.37ꢀ1.44 (m, 2H), 1.47ꢀ1.56 (m, 4H), 2.43ꢀ2.52 (m, 4H), 3.97 (q, J = 6.6 Hz, 1H), 7.3 (t, J
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= 7.8 Hz, 1H), 7.47ꢀ7.51 (m, 1H), 8.00 (d, J = 7.8 Hz, 1H), 8.13 (t, J = 1.8 Hz, 1H). C NMR (75
MHz, CDCl3): δ 10.2, 24.3, 26.3, 50.6, 65.6, 127.1, 129.1, 129.5, 132.5, 134.3, 137.9, 199.6.
2ꢀPiperidinꢀ1ꢀ(4ꢀfluorophenyl)propanꢀ1ꢀone (3p) Yield: 176 mg, 75 %; Brown oil; Flash
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chromatography (petroleum ether/ethyl acetate, 2/1); H NMR (CDCl3, 300 MHz): δ 1.23 (d, J =
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6.9 Hz, 3H), 1.37ꢀ1.43 (m, 2H), 1.49ꢀ1.56 (m, 4H), 2.43ꢀ2.55 (m, 4H), 3.97 (q, J = 6.6 Hz, 1H),
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7.06ꢀ7.12 (m, 2H), 8.16ꢀ8.21 (m, 2H); C NMR (CDCl3, 75 MHz): δ 10.5, 24.3, 26.3, 50.7, 65.7,
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115.0 (d, J(C,F) = 21.4 Hz ), 131.6 (d, J(C,F) = 9.0 Hz ), 132.7 (d, J(C,F) = 3.1 Hz ), 163.8 (d,
J(C,F) = 252.6 Hz ), 199.4. HRMS (ESI) m/z calcd for C14H19FNO(M+H)+ 236.1445, found
236.1443.
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2ꢀPiperidinꢀ1ꢀ(4ꢀmethylphenyl)propanꢀ1ꢀone (3q)10b Yield: 120 mg, 52 %; Brown oil; Flash
chromatography(petroleum ether/ethyl acetate, 5/1); 1H NMR (300 MHz, CDCl3) δ 1.24 (d, J = 6.9
Hz, 3H), 1.37ꢀ1.42 (m, 2H), 1.45ꢀ1.52 (m, 4H), 2.40 (s, 3H), 2.48ꢀ2.55 (m, 4H), 4.04 (q, J = 6.9 Hz,
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1H), 7.23(d, J = 8.1 Hz, 2H), 8.01 (d, J = 8.1 Hz, 2H); C NMR (75 MHz, CDCl3): δ 11.5, 21.6,
24.4, 26.3, 50.8, 65.0, 128.9, 129.0, 134.0, 143.5, 200.7.
2ꢀPiperidinꢀ1ꢀ(3ꢀmethylphenyl)propanꢀ1ꢀone (3r)6b Yield: 127 mg, 55 %; Brown oil; Flash
chromatography(petroleum ether/ethyl acetate, 5/1); 1H NMR (300 MHz, CDCl3): δ 1.24 (d, J = 6.6
Hz, 3H), 1.37ꢀ1.45 (m, 2H), 1.47ꢀ1.53 (m, 4H), 2.40 (s, 3H), 2.45ꢀ2.59 (m, 4H), 4.05 (q, J = 6.8 Hz,
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1H), 7.31ꢀ7.34 (m, 2H), 7.88ꢀ7.93 (m, 2H); C NMR (75 MHz, CDCl3): δ 11.6, 21.4, 24.4, 26.3,
50.8, 64.9, 126.0, 128.1, 129.2, 133.5, 136.6, 138.0, 201.3.
2ꢀPiperidinꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (3s)10f Yield: 124 mg, 50 %; Brown oil; Flash
chromatography(petroleum ether/ethyl acetate, 5/1); 1H NMR (300 MHz, CDCl3): δ 1.24 (d, J = 6.6
Hz, 3H), 1.37ꢀ1.42 (m, 2H), 1.50ꢀ1.54 (m, 4H), 2.43ꢀ2.57 (m, 4H), 3.86 (s, 3H), 3.98 (q, J = 6.9 Hz,
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1H), 6.90 (d, J = 9.0 Hz, 2H), 8.12 (d, J = 8.7 Hz, 2H). C NMR (75 MHz, CDCl3): δ 11.5, 24.4,
26.3, 50.8, 55.4, 65.2, 113.3, 129.4, 131.2, 163.1, 199.7.
2ꢀPiperidinꢀ2ꢀCyclopropylꢀ1ꢀphenylꢀ1ꢀethanone (3w) Yield: 109 mg, 45 %; Brown oil; Flash
chromatography(petroleum ether/ethyl acetate, 1/1); 1H NMR (300 MHz, CDCl3): δ 0.04ꢀ0.11 (m, 1
H), 0.37ꢀ0.40 (m, 1 H), 0.70ꢀ0.74 (m, 1 H), 1.09ꢀ1.12 (m, 1 H), 1.44ꢀ1.46 (m, 2 H), 1.44ꢀ1.57 (m, 4
H), 2.38ꢀ2.41 (m, 2 H), 2.66ꢀ2.69 (d, J = 9.6 Hz, 1 H), 2.79ꢀ2.80 (m, 2 H), 7.41ꢀ7.46 (m, 2 H),
7.52ꢀ7.56(m, 1 H), 8.29ꢀ8.31 (m, 2 H). 13C NMR (75MHz, CDCl3): δ 1.6, 7.3, 10.9, 24.5, 26.1, 52.6,
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79.5, 128.2, 129.2, 132.8, 136.5, 200.1. HRMS (ESI) m/z calcd for C16H22NO (M+H)+ 244.1696,
found 244.1694.
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2ꢀIodoꢀ1ꢀphenylpropanꢀ1ꢀone (4a). 1H NMR(CDCl3, 300 MHz): δ 2.07(d, J = 6.6 Hz, 3H), 5.50(q,
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J = 6.6 Hz, 1H), 7.51(t, J = 8.0 Hz, 2H), 7.63(t, J = 8.0 Hz, 1H), 7.99(d, J = 6.8, 2H); C NMR
(CDCl3, 75 MHz): δ 18.1, 22.0, 128.6, 128.7, 133.4, 133.5, 194.7. HRMS (ESI) m/z calcd for
C9H10IO (M+H)+ 260.9771, found 260.9779.
2ꢀhydroxylꢀ1,1ꢀdimethoxypropylbenzene: 1H NMR (CDCl3): δ 0.96 (d, J = 6.3 Hz 3H ), 2.41 (dr,
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1H), 3.22 (s, 3H), 3.37 (s, 3H), 4.11 (q, J = 6.3 Hz, 1H), 7.26ꢀ7.48 (m, 5H). C NMR (CDCl3): δ
16.4, 49.3, 50.0, 70.7, 103.5, 127.7, 128.0, 128.0, 137.3.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No.
21272021, 21472011) and the national key research and development program (2016YFD0400801).
ZCC and SBG are grateful to Beijing advanced innovation center for food nutrition and human
health for fostering our collaboration.
The authors declare no competing financial interest.
Supporting Information Available: Copies of 1H, 13C NMR spectral of related starting material
and products, cyclic voltammetry of redox catalyst and GCꢀMS monitored control reactions
between 1a and 2a and cyclic voltammetry of redox catalyst. This material is available free of
charge via the Internet at http://pubs.acs.org
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