Electrochemical synthesis of amides: Direct transformation of methyl ketones with formamides

Article abstract of DOI:10.1016/j.tetlet.2013.10.101

A direct transformation from methyl ketones to secondary or tertiary amides has been developed through a novel electrochemical approach and a wide scope of formamides could be utilized as the amide sources. This transformation was promoted by in situ generated iodine through electrolysis of sodium iodide under mild, metal-free conditions. This electrochemical procedure could avoid the use of stoichiometric iodine and afforded the target products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.10.101

Tetrahedron Letters 54 (2013) 7156–7159
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Electrochemical synthesis of amides: direct transformation
of methyl ketones with formamides
⇑
Haolai Huang, Gaoqing Yuan , Xianwei Li, Huanfeng Jiang
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2013
Revised 17 October 2013
Accepted 21 October 2013
Available online 26 October 2013
A direct transformation from methyl ketones to secondary or tertiary amides has been developed through
a novel electrochemical approach and a wide scope of formamides could be utilized as the amide sources.
This transformation was promoted by in situ generated iodine through electrolysis of sodium iodide
under mild, metal-free conditions. This electrochemical procedure could avoid the use of stoichiometric
iodine and afforded the target products in good to excellent yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Electrosynthesis
Amides
Ketones
Formamides
The amide formation is an important reaction in chemical syn-
thesis, since the amide functional group is an essential motif in
natural products, polymers, and pharmaceuticals.1 The traditional
synthesis of amides is started from an activated carboxylic acid
and an amine.2 Alternative methods such as condensation of ni-
triles with amines,3 addition of formamides to alkenes or
alkynes,4,5 the aminocarbonylation of aryl halides,6 and oxidation
of alcohols in the presence of aqueous ammonia have been uti-
lized.7 In addition, catalytic acylation of amines with aldehydes un-
der oxidative conditions could serve as amide synthesis.8 Another
attractive approach is the transition-metal-catalyzed C–C bond
cleavage based amidation.9 Furthermore, iodine-promoted trans-
formation of methyl ketones with aqueous ammonia to the corre-
sponding primary amides through C–C bond cleavage has been
reported.10 Due to limited substrate scope, the progress of this
methodology is hampered thus far. Further application of this
methodology for the synthesis of various secondary and tertiary
amides is still unexplored.
to access amides via an electrochemical route has been put
forward. Although both the C–C bond cleavage of ketones and
the decarbonylation of DMF have been well-documented,10,13 inte-
gration of these two transformations into an amide bond via an
electrochemical route in the absence of metal catalyst remains
unexplored.
Our study started from the condensation of acetophenone 1a
with dimethylamine in an undivided cell fitted with inert graph-
ite anode and nickel cathode. NH4I was employed as the support-
ing electrolyte. Trace N,N-dimethyl-benzamide was obtained
Table 1
Transformation of ketone with dimethylaminea
O
O
electrolysis
+
NHMe2
NMe2
3a
Solvent
1a
The electrochemical method has been widely applied to the
chemical transformations, due to its mildness, high efficiency,
and environmentally friendly characteristics.11 The advantage of
electrosynthesis includes mild electron-transfer conditions to
achieve oxidation and reduction reactions, and circumvention of
the use of hazardous or toxic oxidants. In the course of our contin-
uing studies on organic electrosynthesis,12 a novel transformation
Entry
Anode–cathode
Supporting electrolyte
Yieldb (%)
1
2
3
4
5
6
C—Ni
C—Ni
C—Ni
C—Ni
C—Ni
C—Ni
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
MeOH
MeCN
THF
CH2Cl2
DMSO
DMF
Trace
0
0
Trace
32
65
a
Reaction conditions: 1a (1.0 mmol), dimethylamine (5.0 mmol), solvent (8 mL),
supporting electrolyte (0.5 mol LÀ1), undivided cell, current 50 mA, 6 h and rt.
Isolated yields.
⇑
Corresponding author.
E-mail address: gqyuan@scut.edu.cn (G. Yuan).
b
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.101

H. Huang et al. / Tetrahedron Letters 54 (2013) 7156–7159
7157
Table 2
smoothly transformed into the desired products (3aa–3ma).
Generally, ketones bearing electron-withdrawing substituents
(1b–1j) gave higher yields than those with electron-donating sub-
stituents (1k–1m). Furthermore, substituents at different positions
on the arene group (para, meta, and ortho positions) affect the reac-
tion efficiency. For example, the reaction proceeded efficiently
when ortho- and para-substituted on the benzene ring were em-
ployed (1c,1f). However, meta-substituents had a negative effect
on the transformation (1g), and gave only 71% yield. Heteroaryl
(furan (1o,1q) and thiophene (1p)) methyl ketones could also be
transformed into the desired products under the optimized condi-
tions. Similarly, 1-acetonaphthone also exhibited a moderate yield
of the desired product (1n). Moreover, different N-substituted for-
mamides including N-methylformamide, N-phenylformamide, and
N-tert-butylformamide were applied in the current conditions and
the corresponding products could be obtained in moderate to high
yields (2b–2d). Notably, cyclic formamides such as 1-formylpiperi-
dine, 4-formylmorpholine, and 1-formylpyrrole were also suitable
partners to provide the desired results (2f–2h). However, sterically
hindered formamides such as N,N-dibutyl formamide and N-
methyl-N-phenylformamide afforded lower yields (2e,2i), indicat-
ing that the steric effect is an important factor of the transforma-
tion. In addition, it should be pointed out that some by-products
(such as dimethyl sulfone) were consistently formed in the present
electrolytic conditions. Obviously, the side reaction on the anode
(the oxidation of DMSO to dimethyl sulfone) would consume a part
of the electrolytic electricity so that the current efficiency of the
target products was relatively low (around 50%).
Optimization of the reaction conditionsa
O
O
O
electrolysis
+
H
NMe2
2a
NMe2
1a
3aa
Solvent
Entry
Anode–cathode
Supporting electrolyte
Yieldb (%)
1
2
3
4
5
6
7
8
C—Ni
C—Ni
C—Ni
C—Ni
C—Ni
C—Ni
C—Ni
C—Ni
C—Ni
C—Ni
C—Cu
C—Al
C—Zn
NH4I
n-Bu4NI
KI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
DMSO
DMSO
DMSO
DMSO
THF
MeCN
MeOH
CH2Cl2
DMSO
DMSO
DMSO
DMSO
DMSO
72
15
30
92
32
Trace
20
Trace
68c
Traced
82
9
10
11
12
13
85
86
a
Reaction conditions: 1a (1.0 mmol), 2a (5.0 mmol), solvent (8 mL), supporting
electrolyte (0.5 mol LÀ1), undivided cell, current 50 mA, 6 h, and rt.
Isolated yield based on 1a.
b
c
Supporting electrolyte (0.25 mol LÀ1).
d
Dried DMSO.
when MeOH, MeCN, THF, or CH2Cl2 was used as solvents (Table 1).
Interestingly, when the solvent was replaced by DMSO or DMF,
N,N-dimethylbenzamide (3aa) was obtained in 32% and 65%
yields, respectively. In order to confirm whether the amine was
generated in situ from DMF, dimethylamine was replaced with
DMF. It was found that 3aa was obtained in 72% yield (Table 2,
entry 1). Inspired by this observation, we further studied the
unexpected reaction for the synthesis of benzamides. Acetophe-
none (1a) and DMF (2a) were chosen as model substrates to
optimize the reaction conditions. As shown in Table 2, among
the supporting electrolytes tested, NaI was the most effective
(entry 4). Other supporting electrolytes such as n-Bu4NI and KI
could not afford comparable results (entries 2 and 3). At the same
To obtain a better understanding of the mechanism of the reac-
tion, control experiments were performed (Scheme 2). With
dimethylamine as the substrate, the reaction could proceed
smoothly, affording the corresponding product 3aa in 47% yield
(Eq. 2). In addition, sodium p-toluenesulfinate could react with
DMF to give 4 in 80% yield (Eq. 1), indicating that DMF could read-
ily lose a carbonyl group under the present electrochemical condi-
tions. Based on these experimental results, we reasoned that the
carbonyl group of the target product 3 was from 1 rather than
formamide.
+
iodide anion (IÀ), different cations (Na+, NH4 and n-Bu4N+) lead
to different results. This may be closely related to the reducibility
of these cations. In the present electrochemical conditions, NH4
According to the above results, a possible mechanism is pro-
posed in Scheme 3. IÀ ions could be oxidized to I2 at the graphite
anode (2IÀ ? I2 + 2eÀ).11f The resultant I2 could react with aceto-
+
or n-Bu4N+ ions were easily electroreduced to generate NH3 or or-
ganic amines,12d,14 which resulted in the formation of by-prod-
ucts such as benzamide. With KI as the supporting electrolyte, a
large quantity of undetermined colloidal by-product was
observed. The difference between NaI and KI supporting
electrolyte is not fully understood at the present stage. Subse-
quently, we tested the reaction in the presence of different sol-
vents. Further investigations revealed that solvents also play a
pivotal role in this transformation. DMSO was superior to any
other solvents (entries 4–8), while MeCN and CH2Cl2 gave only
a trace amount of the desired product. Notably, the reaction
was sluggish when extra-dried DMSO was employed (entry 10),
which revealed that a small amount of water was crucial for this
reaction. The yields dropped from 92% to 68% when the mole
ratios between NaI and acetophenone were changed from 4:1 to
2:1 (entry 9). Ultimately, several electrode materials including
Cu, Al, and Zn were investigated to assess the effect of the
transformation of acetophenone in the same condition (entries
11–13), and these electrode materials were suitable for this
reaction as well.
phenone 1a to form
a,a,a-triiodomethyl ketone B, via a Lieben
iodoform reaction.10 Meanwhile, the electro-reduction of 2 at the
cathode generates amine A. Further,
a,a,a-triiodomethyl ketone
B is attacked by the amine A to form intermediate C,15 which could
subsequently release iodoform and the desired product 3. The for-
mation of iodoform could be observed during our experiments (see
the Supplementary data).
In conclusion, a novel electrochemical synthesis of secondary
and tertiary amides from ketones and formamides has been dem-
onstrated. The electrochemical system composed of NaI and DMSO
has shown high efficiency in the direct amidation of methyl ke-
tones and formamides under mild, metal-free conditions. Further
studies on the mechanistic details and synthetic application of this
reaction are underway in our laboratory.
Acknowledgments
We thank the National Natural Science Foundation of China
(21172079), the Science and Technology Planning Project of
Guangdong Province (2011B090400031), the National Basic Re-
search Program of China (973 Program, 2011CB808600), and
Guangdong Natural Science Foundation (10351064101000000)
for financial support.
Under the optimized conditions, the substrate scope of the reac-
tion was investigated. As shown in Scheme 1, both electron-rich
and electron-deficient aryl methyl ketones (1a–1m) could be

7158
H. Huang et al. / Tetrahedron Letters 54 (2013) 7156–7159
O
O
O
NaI - DMSO
rt
R2
Ni
C
R2
+
R1
N
H
N
R3
R1
R3
1
2
3
O
O
O
O
N
N
N
Br
Cl
F
3ba,95%
3ea,91%
3da,80%
3ca,86%
O
O
N
N
N
I
Cl
O
Cl
3fa,83%
3ia,82%
3la,71%
3ga,71%
O
O
O
O
N
N
N
N
N
N
F3C
NC
O2N
3ja,94%
3ha,87%
O
O
3ka,75%
3na,74%
3ma,77%
O
O
O
O
S
N
N
N
3oa,81%
3pa.84%
O
O
O
N
H
N
H
N
H
3ad,84%
3ac,70%
3ab,87%
O
O
O
O
N
N
N
N
O
3af,64%
3ag,88%
3ae,45%
O
N
3ai,<5%
3ah,78%
Scheme 1. Transformation of methyl ketones with formamides (reaction conditions as shown in Table 2 (entry 4)).
O
S
O
S
NMe2
O
electrolysis, rt
ONa
+
O
H
NMe2
(eq 1)
(eq 2)
4
, 80%
O
standard conditions
3aa
47%
NHMe2
+
Ph
Scheme 2. Control experiments.

H. Huang et al. / Tetrahedron Letters 54 (2013) 7156–7159
7159
Anode
Cathode
O
R2
R1
N
R3
O
CHI3
e-
R
CI3
1 NH
R2
R3
R2
6I-
CO
C
NH
e-
R3
A
O
B
O
3I2
R1
3HI
CI3
R2
O
N
R3
R1
Scheme 3. Proposed mechanism.
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