Direct electrochemical imidation of aliphatic amines via anodic oxidation

Article abstract of DOI:10.1039/c1cc10871a

Direct electrochemical synthesis of sulfonyl amidines from aliphatic amines and sulfonyl azides was realized with good to excellent yields. Traditional tertiary amine substrates were broadened to secondary and primary amines. The reaction intermediates were observed and a reaction mechanism was proposed and discussed.

Full text of DOI:10.1039/c1cc10871a

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COMMUNICATION
Direct electrochemical imidation of aliphatic amines via anodic
oxidationw
Li Zhang,a Ji-Hu Su,b Sujing Wang,b Changfeng Wan,a Zhenggen Zha,*a Jiangfeng Du*b
and Zhiyong Wang*a
Received 15th February 2011, Accepted 21st March 2011
DOI: 10.1039/c1cc10871a
Direct electrochemical synthesis of sulfonyl amidines from aliphatic
amines and sulfonyl azides was realized with good to excellent
yields. Traditional tertiary amine substrates were broadened to
secondary and primary amines. The reaction intermediates were
observed and a reaction mechanism was proposed and discussed.
smoothly dealkylated electrochemically to give an amine of
lower order and an aldehyde. Until now, the continual study
or further investigation of synthetic applications of amine
oxidation is seldom.8 Now, we realized direct electrochemical
imidation of aliphatic amines via anodic oxidation.
At first, the imidation of tertiary amines was investigated.
Intrigued by the previous reports,3–5 we expected that anodic
oxidation can realize the transformation of Et3N to enamine,
which was the key intermediate for imidation. Therefore
the cyclic voltammetry (CV) of Et3N was measured in 0.05 M
n-Bu4NPF6/CH3CN. The value of +1.60 V (vs. SCE) indicated
the oxidation potential of Et3N in acetonitrile.6a,7,9 It was therefore
possible to perform the imidation of Et3N via anodic oxidation.
In a simple electrochemical setup consisting of an undivided
cell equipped with a pair of platinum and carbon-rod electrodes,
the mixture of sulfonyl azide (0.2 mmol) and triethylamine
(0.4 mmol) in 0.05 M n-Bu4NPF6/CH3CN (6 mL) was electro-
lyzed under galvanostatic conditions and stirred simultaneously
for 3 h at room temperature (applied current: 4 mA, current
density: 2.5 mA cmÀ2, 2.2 F molÀ1 of current was consumed.
Caution: Azides and diazoalkanes may be hazardous and/or
explosive). To our delight, the desired sulfonyl amidine was
obtained with a yield of 67% (Table 1, entry 1).10
Amidine derivatives have been widely used in medicinal and
synthetic chemistry due to their unique structure and a variety
of interesting chemical properties.1 Traditional methods for
the synthesis of amidine derivatives are tedious functional
group transformations from some precursors synthesized
beforehand.2 Therefore, novel simple and efficient methods for
the synthesis of amidine derivatives remain a significant
challenge. Recently, Chang et al. reported tandem reactions
of sulfonyl azides, alkynes and secondary amines either inter-
molecularly or intramolecularly.3 Li and co-workers also
reported two kinds of catalytic systems of DEAD and
CuCl–CCl4, respectively, in which sulfonyl azides were
promoted to couple with tertiary amines.4 Our group also
reported a FeCl3 mediated synthesis of sulfonyl amidines from
sulfonyl azides and tertiary amines.5 The disadvantages of
these methods are the use of stoichiometric or catalytic
amounts of catalysts and the limited scope of amines.
The optimization of the reaction conditions was achieved by
screening different solvents and electrodes.9 The standard reaction
The advantage of electrochemical conversion is a mass-free
electron transfer between the electrode and the substrate in the
reactions. Thereby, the waste disposal of a used redox reagent
is fundamentally eliminated.6 The fundamental investigation
of anodic oxidation of amines had been done in the 1960s by
Mann et al.7 They focused on the dealkylation of aliphatic
amines. In electrolyte containing water, aliphatic amines are
Table 1 Direct electrochemical imidation of triethylamine with
substituted sulfonyl azidesa
Entry
R
Time/h
Yieldb (%)
1
2
3
4
5
6
7
8
4-CH3–C6H4
4-CH3–C6H4
Ph
4-CH3O–C6H4
4-Br–C6H4
4-NO2–C6H4
3-NO2–C6H4
2-NO2–C6H4
2,6-di-Br–C6H3
2-thienyl
3
3
3
4
3
4
3
3
3
3
3
67c
96
94
87
89
82
92
80
92
78
80
a Hefei National Laboratory for Physical Sciences at Microscale,
CAS Key Laboratory of Soft Matter Chemistry, Joint Laboratory of
Green Synthetic Chemistry and Department of Chemistry, University
of Science and Technology of China, Hefei, 230026, P. R. China.
E-mail: zwang3@ustc.edu.cn, zgzha@ustc.edu.cn;
Fax: +86-551-3603185; Tel: +86-551-3603185
b Hefei National Laboratory for Physical Sciences at Microscale and
Department of Modern Physics, University of Science and
Technology of China, Hefei, 230026, P. R. China.
9
10
11
E-mail: djf@ustc.edu.cn; Fax: +86-551-3600039;
Tel: +86-551-3600039
Camphoryl
a
b
w Electronic supplementary information (ESI) available: Typical
experimental procedure along with the capture of intermediates and
characterization data of all products. See DOI: 10.1039/c1cc10871a
Reaction conditions: for details see ESI.w Isolated yield based on
sulfonyl azide. Pt as anode and graphite as cathode.
c
c
5488 Chem. Commun., 2011, 47, 5488–5490
This journal is The Royal Society of Chemistry 2011

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Table 2 Reaction of sulfonyl azide with different tertiary aminesa
Entry
Tertiary amine
Product
Yieldb (%)
1
2
n-Pr3N
94
82
i-Pr2NEt
3
4
68
76c
52
5
a
b
Reaction conditions: for details see ESI.w Isolated yield based on
TsN3. Electrolysis time was 4 h.
c
Scheme 1 Proposed mechanism for the imidation of (a) triethylamine
(b) diethylamine.
condition was established as follows: CH3CN as the solvent,
Bu4NPF6 as the electrolyte, graphite as both anode and cathode.
Under the optimized conditions, various substituted sulfonyl
azides were investigated to expand the scope and generality of
this reaction system, as shown in Table 1. Aromatic sulfonyl
azides with either electron-donating or electron-withdrawing
groups on the phenyl ring worked well and the corresponding
products were obtained with good to excellent yields (Table 1,
entries 2–9). A slight electronic effect can be observed when the
nitro group located on different positions of the phenyl ring
(Table 1, entries 6–8). The location of the nitro group at the meta
position favored this reaction. The sulfonyl azide with a hetero-
aromatic ring and aliphatic sulfonyl azide also performed well
(Table 1, entries 10–11). Afterwards, different aliphatic tertiary
amines were investigated (Table 2). When tertiary amines were
composed of three equivalent aliphatic chains, only one kind of
sulfonyl amidine could be formed (Table 1 and 2, entry 1). It was
noted that only one kind of sulfonyl amidine was obtained in the
cases of N,N-diisopropylethylamine (Table 2, entry 2) and cyclic
tertiary amines (Table 2, entries 3–5) in spite of two kinds of alkyl
groups in these amines. N,N-Diisopropylethylamine was reacted
on ethyl instead of an isopropyl group while cyclic tertiary
amines were reacted on the cyclic a-C to give the corresponding
products. This indicated that the imidation of cyclic tertiary
amines had a good selectivity under electrochemical conditions.
Afterwards, the reaction mechanism was investigated. The
electrolysis of TsN3 or Et3N was performed separately.9 The
experimental results demonstrated that only Et3N was
the electroactive substrate in this reaction. According to the
experimental results and existing literature,6a,b,7 a possible
mechanism is presented in Scheme 1(a). First, Et3N is oxidized
to the cation radical A, which is deprotonated to produce
radical B and further oxidized to give the iminium ion C.
Cation radical A was found when the X-band EPR measure-
ment was conducted at room temperature and the result is
shown in Fig. 1.9 Under alkaline conditions, iminium ion C
can be further deprotonated to yield enamine D, which is
Fig. 1 The X-band (9.7 GHz) cw-EPR spectrum of radical A (red) in
Scheme 1, and the simulation (blue). For simulation, the principal
parameters are g-value of 2.0022, the isotropic hyperfine constants
(A1H and A14N) of 30.98 and 43.69 MHz for the 1H and 14N respectively.
captured by 2,4-dinitrophenylhydrazine.9 Subsequently, 1,3-
dipolar cycloaddition between D and TsN3 followed by the
release of one molecule of CH2N2 finally gives rise to sulfonyl
amidine. The CH2N2 is captured by benzoic acid to produce
methyl benzoate.9 To confirm this mechanism, enamine D was
prepared through the conventional method,11 reacting with
sulfonyl azide. The desired sulfonyl amidine was obtained.
After finishing the imidation of tertiary amines, we endeavoured
to extend the scope of tertiary amines to secondary amines. First,
the electrochemical behavior of diethylamine was investigated.9
An oxidation potential of +1.80 V (vs. SCE) of Et2NH in
acetonitrile indicated that it was possible for diethylamine to be
oxidized into enamine.6a,7
To our surprise, diethylamine also proceeded very well and
even the same products as that of triethylamine were obtained
under the same conditions (Table 3). It was found that the
reaction of diethylamine with sulfonyl azides afforded the
corresponding sulfonyl amidines with good to excellent yields
although the strong electron-withdrawing group on the phenyl
ring had a slight negative electronic effect on this reaction
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5488–5490 5489

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Table 3 Direct electrochemical imidation of diethylamine with
substituted sulfonyl azidesa
Entry
R
Time/h
Yieldb(%)
1
2
3
4
5
6
7
8
9
Ph
3
3
4
3
4
3
4
3
4
91
93
84
91
73
82
65
89
64
4-CH3–C6H4
4-CH3O–C6H4
4-Br–C6H4
4-NO2–C6H4
3-NO2–C6H4
2-NO2–C6H4
2,6-di-Br–C6H3
2-Thienyl
Scheme 2 Reaction of sulfonyl azide with primary amines.
were obtained with moderate yields. The products were also
the mixture of Z and E configurations.
In summary, a promising new electrochemical strategy for
the synthesis of sulfonyl amidine derivatives was developed.
Traditional tertiary amine substrates were broadened to
secondary and primary amines. By virtue of this electro-
chemical method, the waste disposal of a used redox reagent
is fundamentally eliminated and the reaction is carried out
under mild conditions. Several intermediates were observed
and the corresponding mechanisms were proposed. The
current advances promise continuing interest in application
of this method in modern synthesis.
a
b
Reaction conditions: for details see ESI.w Isolated yield based on
sulfonyl azide.
Table 4 Reaction of sulfonyl azide with different secondary aminesa
Entry
Amine
Product
Z/E
Yieldb (%)
We thank the National Natural Science Foundation of
China (No. 20772118, 90813008, 20932002, 20972144) and
Department of Education (9850290071) for support.
1
2
Et2NH
E
93
62
n-Pr2NH
1 : 2
Notes and references
3
i-Pr2NH
—
0
1 (a) G. V. Boyd, in The Chemistry of Amidines and Imidates, ed.
S. Patai and Z. Rappoport, Wiley, New York, 1991, vol. 2, ch. 8;
(b) J. Barker and M. Kilner, Coord. Chem. Rev., 1994, 133, 219.
2 (a) T. Takuwa, T. Minowa, J. Y. Onishi and T. Mukaiyama,
Bull. Chem. Soc. Jpn., 2004, 77, 1717; (b) N. Kumagai,
S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed., 2004,
4
5
n-Bu2NH
1 : 5
1 : 2
55
82
43, 478; (c) U. E. W. Lange, B. Schafer, D. Baucke, E. Buschmann
¨
and H. Mack, Tetrahedron Lett., 1999, 40, 7067.
a
b
Reaction conditions: for details see ESI.w Isolated yield based on
TsN3.
3 (a) S. Chang, M. Lee, D. Y. Jung, E. J. Yoo, S. H. Cho and
S. K. Han, J. Am. Chem. Soc., 2006, 128, 12366; (b) I. Bae, H. Han
and S. Chang, J. Am. Chem. Soc., 2005, 127, 2038.
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N. Yao and X. N. Li, Org. Lett., 2010, 12, 897; (b) X. L. Xu, X. N. Li,
L. Ma, N. Ye and B. J. Weng, J. Am. Chem. Soc., 2008, 130, 14048.
5 S. J. Wang, Z. Y. Wang and X. Q. Zheng, Chem. Commun., 2009,
7372.
6 (a) Organic Electrochemistry, ed. H. Lund and O. Hammerich,
Marcel Dekker, New York, 4th edn, 2001; (b) J. Grimshaw,
Electrochemical Reactions and Mechanisms in Organic Chemistry,
Elsevier, Amsterdam, 2000; (c) J. Yoshida, K. Kataoka,
R. Horcajada and A. Nagaki, Chem. Rev., 2008, 108, 2265;
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7 (a) R. F. Dapo and C. K. Mann, Anal. Chem., 1963, 35, 677;
(b) C. K. Mann, Anal. Chem., 1964, 36, 2424; (c) K. K. Barnes and
C. K. Mann, J. Org. Chem., 1967, 32, 1474; (d) P. J. Smith and
C. K. Mann, J. Org. Chem., 1968, 33, 316; (e) P. J. Smith and
C. K. Mann, J. Org. Chem., 1969, 34, 1821; (f) L. C. Portis
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(Table 3, entries 5–7). Subsequently, various secondary amines
were examined, as shown in Table 4. It was noted that both
triethylamine and diethylamine gave the same product with E
configuration. However, the other kinds of aliphatic secondary
amines generated the sulfonyl amidines with the mixture of Z
and E configuration. The ratios of Z/E for different amines are
1 : 2, 1 : 5 and 1 : 2 respectively (Table 4, entries 2, 4 and 5).
As for diisopropylamine, the corresponding sulfonyl amidine
was not obtained, probably due to the steric hindrance and the
electronic effect of the diisopropyl group (Table 4, entry 3).
The mechanism of imidation of diethylamine was also
proposed as shown in Scheme 1(b). First, diethylamine is
oxidized to form enamine D1 through the same route as
triethylamine. Enamine D1 exchanges with diethylamine to
give enamine D with release of one molecule of ethylamine.12
Ethylamine was captured by benzaldehyde and was detected
by GC-MS.9 Enamine D was also the intermediate of imida-
tion of triethylamine. Then enamine D afforded the same
product for diethylamine as that of triethylamine by 1,
3-dipolar cycloaddition with sulfonyl azide. According to this
mechanism (Scheme 1), we expected the primary amines could
produce similar sulfonyl amidines as that of secondary amines.
Therefore, propylamine and butylamine were examined
(Scheme 2). As expected, the corresponding sulfonyl amidines
9 Details are provided in ESIw.
10 Without electrolysis, the sulfonyl amidine was not obtained, and
TsN3 was recovered.
11 P. L.-F. Chang and D. C. Dittmer, J. Org. Chem., 1969, 34, 2791.
12 R. F. Abdulla, K. H. Fuhr and J. C. Williams, Jr, J. Org. Chem.,
1979, 44, 1349.
c
5490 Chem. Commun., 2011, 47, 5488–5490
This journal is The Royal Society of Chemistry 2011