A facile sp3C–H bonds amidation of N,N-dimethylanilines by a novel ionic iron(III) complex containing an imino-functionalized imidazolium cation

Article abstract of DOI:10.1016/j.tetlet.2016.07.098

A new imino-functionalized imidazolium salt, 1-[1-(2,6-diisopropylphenylimino)ethyl]-3-benzylimidazolium chloride ([HL]Cl,), was designed and used to prepare a novel ionic iron(III) complex [HL][FeCl₄] (2). Complex 2 was an efficient and easy-t

Full text of DOI:10.1016/j.tetlet.2016.07.098

Accepted Manuscript
A facile sp3 C-H bonds amidation of N,N-dimethylanilines by a novel ionic
iron(III) complex containing an imino-functionalized imidazolium cation
Fan Zhu, Bing Lu, Hongmei Sun, Qi Shen
PII:
S0040-4039(16)30966-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.098
TETL 47960
Reference:
Tetrahedron Letters
To appear in:
Received Date:
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Accepted Date:
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16 July 2016
30 July 2016
Please cite this article as: Zhu, F., Lu, B., Sun, H., Shen, Q., A facile sp3 C-H bonds amidation of N,N-
dimethylanilines by a novel ionic iron(III) complex containing an imino-functionalized imidazolium cation,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.098
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Tetrahedron Letters
A facile sp3 C-H bonds amidation of N,N-dimethylanilines by a novel ionic iron(III)
complex containing an imino-functionalized imidazolium cation
Fan Zhu, Bing Lu, Hongmei Sun and Qi Shen
The Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou
215123, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new imino-functionalized imidazolium salt, 1-[1-(2,6-diisopropylphenylimino)ethyl]-3-
benzylimidazolium chloride ([HL]Cl,), was designed and used to prepare a novel ionic iron(III)
complex [HL][FeCl4] (2). Complex 2 was an efficient and easy-to-use catalyst for the direct sp3
C-H bonds amidation of N,N-dimethylanilines, affording a wide variety of N-substitued aromatic
or aliphatic amides in moderate to good yields. This reaction is the first example of iron-
catalyzed intermolecular amidation of unactivated sp3 C-H bonds of tertiary amines by aromatic
or aliphatic amides under mild reaction conditions.
Available online
Keywords:
Iron(III) complex
Imidazolium salts
Amidation of C-H bond
N,N-Dimethylanilines
2016 Elsevier Ltd. All rights reserved.
1. Introduction
developed an FeCl2.4H2O/bipyridine/TBHP system for the direct
amidation of the sp3 C–H bonds adjacent to nitrogen atoms of
tertiary amides.12 To the best of our knowledge, there has been no
systematic study of iron-catalyzed oxidative cross-coupling of
tertiary amines with amides, that proceed by amidation of
unactivated sp3 C–H bonds adjacent to nitrogen atoms in tertiary
amines.6
The development of novel methods for the construction of C–
N bonds is an important and long-standing research topic in
organic synthesis because nitrogen-containing functional groups
are ubiquitous in natural products, bioactive molecules and
functional materials.1 In the past two decades, transition-metal-
catalyzed direct amidation of sp3 C–H bonds has emerged as an
attractive strategy for the C–N bond formation in terms of
sustainablity.2 In this context, good progress has recently made in
copper3-7- or cobalt8-catalyzed intermolecular amidation of sp3
C–H bonds, including allylic and/or benzylic sp3 C–H bonds,3-5,8
sp3 C–H bonds adjacent to a nitrogen atom3b,6 and even
unactivated sp3 C–H bonds in alkanes,5,7 using simple amide
reagents via oxidative cross-coupling of C–H and N–H bonds.3-8
These amidation reactions open up new opportunities that
complement metal–nitrene amidation protocols in that both
primary and secondary amides can be used as coupling partners.2a
In addition, transition-metal-free intermolecular amidation of
allylic and benzylic sp3 C–H bonds have also been developed.9
As a continuation of our studies on the development of iron-
based catalysis for C–C bond formation,13-15 we now report the
use of an imino-functionalized imidazolium salt 1 in the facile
synthesis of a novel ionic iron(III) complex 2, and the use of 2 as
an efficient catalyst for the sp3 C–H bond amidation of N,N-
dimethylanilines.
A
series of readily available imino-
functionalized imidazolim salts have shown great potential in
several catalytic systems, including rhodium-based systems for
cyclopropanation reactions,16 palladium-based systems for
Suzuki–Miyaura cross-coupling reactions,17 direct arylation of
electron-deficient
fluoroarenes18
and
norbornene
polymerization.19 However, their potential use in iron-based
catalytic systems remains poorly explored.20
Significant effort has been devoted to the development of
iron-catalyzed C–H bond functionalization because iron is
abundant inexpensive, nontoxic, and environmentally benign,
and therefore, provides “greener” strategies for organic
synthesis.10 Until now only two papers describing the iron-
catalyzed intermolecular amidation of sp3 C–H bonds have been
published. In 2008, Fu and co-workers reported the first example
of the direct amidation of benzylic sp3 C–H bonds using an
2. Results and discussion
2.1 Synthesis and characterization of 1 and 2
A novel imino-functionalized imidazolium chloride, 1-[1-(2,6-
diisopropylphenylimino)ethyl]-3-benzylimidazolium
chloride
published
([HL]Cl, 1), was readily synthesized using
a
procedure.16 As shown in Scheme 1 (Eq. 1), 1 was obtained in
FeCl2/NBS catalyst/oxidant system.11 Recently, Zhu et al.
90% yield as a white solids with considerable air and moisture
———
 Corresponding author. Tel.: +86-512-65880330; e-mail: sunhm@suda.edu.cn

hydrogen-bonding interaction between the [FeCl4] anion and
imidazolium [HL]+ cation, although such interactions occur
widely in other imidazolium-based ionic iron(III) complexes.13,22
stabilities. The elemental analysis results, NMR spectrum, and
ESI mass spectrum of 1 are consistent with its molecular
formula. The most significant feature in the 1H NMR spectrum of
1 is the signal assigned to the imidazolium proton (C2-H), at
12.56 ppm.
Cl
N
Ar
N
THF
N
N
+
N
Ar
(1)
N
25 oC, 24 h
Cl
Ar = 2,6-iPr2C6H3
[HL]Cl (1), Yield: 90%
FeCl4
N
THF
N
Ar
[HL]Cl
+
FeCl3
(2)
N
r.t., 3 h
Ar = 2,6-iPr2C6H3
[HL][FeCl4] (2), Yield: 92%
Scheme 1 Synthesis of [HL]Cl (1) and [HL][FeCl4] (2)
The target ionic iron(III) complex 2 was isolated in 92% yield
from the reaction of anhydrous FeCl3 with 1 equiv of 1 in THF at
room temperature, as shown in Scheme 1 (Eq. 2). Although
anhydrous FeCl3 is highly hydrophilic, complex 2 was obtained
as a hydrophobic and air-stable yellow solid, therefore it was
easy to handle.
Figure 2 Molecular structure of complex 2 with thermal
ellipsoids at the 30% probability level. Selected bond lengths (Å)
and angles (o): Fe(1)Cl(1) 2.1929(9), Fe(1)Cl(2) 2.1896(9),
Fe(1)Cl(3) 2.1906(9), Fe(1)Cl(4) 2.1686(8); Cl(1)Fe(1)
Cl(2)
111.45(4),
Cl(1)Fe(1)Cl(3)
108.79(4),
Cl(1)Fe(1)Cl(4) 111.40(4), Cl(2)Fe(1)Cl(3) 106.47(4),
Cl(2)Fe(1)Cl(4) 109.63(4), Cl(3)Fe(1)Cl(4) 108.94(5).
2.2 Catalysis with complex 2
The reaction shown in Table 1 was chosen as a model system
for initial investigation of the catalysis conditions, it is a
prototypical sp3 C–H bond amidation of tertiary amines catalyzed
by copper-based catalysts.3b,6 The desired product 5aa was
obtained in 78% yield under the initial conditions (entry 4). In
comparison, FeCl3 alone or a mixture of FeCl3 and imidazolium
salt 1 in a 1:1 molar ratio showed moderate activity, and gave
5aa in 53% and 60% yields, respectively (entries 2 and 3). The
use of other oxidants such as DTBP, NBS and DDQ gave no
product, although they are well-known oxidants in C–H bond
functionalization (entries 57). Other solvents (DMSO, CH3CN,
CH3OH and THF) were also investigated (entries 4 and 811),
higher yields were obtained with CH3CN, CH3OH, or EtOAc as
the solvent. We chose EtOAc as the solvent because it is cheap
and has low toxicity. The yield of 5aa increased to 83% when the
temperature was raised to 40 °C (entry 12). Optimization of the
amounts of TBHP and 3a, and the reaction time, showed that the
target product 5aa could be obtained in 93% yield (entry 13). The
optimal conditions for the direct amidation of sp3 C–H bonds
were therefore established to be ionic iron(III) complex 2 (10
mol%), TBHP (1.5 equiv relative to 4a) in EtOAc at 40 °C,
without exclusion of air. The catalytic activity of 2 was compared
with those of previously reported copper-based systems. In
general, 520 mol% loadings of copper(I) salts or a higher
temperature (80 °C) were needed to achieve satisfactory
yields.3b,6 These results show that 2 is an alternative greener
catalyst for sp3 C–H bonds amidation of tertiary amines.
Figure 1 Raman spectra of [HL]Cl (1) and [HL][FeCl4] (2)
Complex 2 was characterized using elemental analysis, Raman
spectroscopy, UV-Vis spectroscopy, electrospray ionization mass
spectroscopy (ESI-MS) and X-ray crystallography. The Raman
spectrum of 2 (Figure 1) shows the presence of [FeCl4] anions,
based on the strong peak at 333 cm-1.21 The bands between 200
and 1800 cm-1 are similar to those in the Raman spectrum of 1,
indicating the presence of the [HL]+ cation in 2. The presence of
the imino-functionalized imidazolium cation was confirmed
based on the positive ion ESI-MS spectrum of 2, which has an
[HL]+ peak of intensity almost 100%. The 1H NMR spectrum of 2
was less informative because the peaks were broad and shifted as
a result of paramagnetism.
Complex 2 was crystallized from cold toluene and examined
using X-ray crystallography. As shown in Figure 2, the solid-
state structure of 2 consists of one [FeCl4] anion and one imino-
functionalized imidazolium [HL]+ cation. The [FeCl4] anion has
a slightly distorted tetrahedral geometry with a mean ClFeCl
angle of 109.5, which is close to the ideal tetrahedral angle of
−50.22 The four FeCl bond distances are in the range
2.1686(8)2.1929(9) Å, in agreement with previously reported
values.14b,c,e The bond distances and angles in the imidazolium
ring and side chain differed only slightly from those in 1-[1-(2,6-
diisopropylphenylimino)ethyl]-3-(2,6-dimethylphenyl)-
Table 1 Optimization of reaction conditionsa
O
NH
O
catalyst / oxidant
solvent
NH2
+
N
N
3a
5aa
4a
Entry
Catalyst
Oxidant (mmol)
TBHPb (1.1)
TBHP (1.1)
TBHP (1.1)
TBHP (1.1)
DTBPb (1.1)
Solvent
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
T (°C)
25
Yield (%)
1
2
3
4
5
1
FeCl3
FeCl3+1
2
trace
53
25
imidazolium chloride reported by Lavoie and co-workers,23 for
example, the mean plane passing through C12C11N3C13 is
slightly twisted from the imidazolium ring by 1.50, and the later one
is oriented nearly perpendicular to the 2,6-diisopropylphenyl ring
with a dihedral angle of 77.35. Notably, there is no discrete
25
60
25
78(61)c
2
25
trace

6
7
2
2
2
2
2
2
2
NBSb (1.1)
DDQb (1.1)
TBHP (1.1)
TBHP (1.1)
TBHP (1.1)
TBHP (1.1)
TBHP (1.1)
EtOAc
EtOAc
DMSO
CH3CN
CH3OH
THF
25
25
25
25
25
25
40
trace
trace
69
13
2
TBHP (1.5)
EtOAc
40
93d (85)d,e
a
Reaction conditions: 3a (1.0 mmol), 4a (0.5 mmol), catalyst (10 mol %),
solvent (2.0 mL), 10 h, in air, yields were determined by 1H NMR using THF
8
as the internal standard.
b TBHP = tert-butyl hydroperoxide (70 wt % aqueous solution), DTBP = tert-
9
76
butyl peroxide, NBS = N-bromosulfonamide, DDQ = 2,3-dichloro-5,6-
10
11
12
79
dicyanobenzoquinone
c 2 (5 mol %).
37
d 3a (0.9 mmol), 8 h.
e Isolated yield.
EtOAc
83
Table 2 Amidation of N,N-dimethylaniline derivatives catalyzed by complex 2a
R3
O
N
O
2 / TBHP
R3
N
+
R2
N
N
R2
R1
EtOAc
R1
H
4
5
3
Entry
1
Aniline
Amide
Product
Yield (%)
85
2
72
3
4
5
61
80
81
NH
N
NO2
6
7
8
72
88
61
O
5af
NH
O
O
N
9
77
5ai
10
11
12
76
72
80

O
13
14
72
72
NH2
4m
15
16
66
76
17
45
18
19
61b
80b
20
60b
21
22
23
78
67
70
24
25
26
67
63c
76c
a Reaction conditions: aniline (0.9 mmol), amide (0.5 mmol), TBHP (0.75 mmol), 2 (10 mol %), EtOAc (2.0 mL), 40 oC, 8 h, in air, isolated yields.
b Aniline (1.1 mmol), 30 oC.
c Aniline (1.0 mmol), 50 oC.
Encouraged by these results, we investigated the scope of
2/TBHP-mediated amidation using our standard conditions. The
data in Table 2 show that this reaction proceeded smoothly for all
the substrates examined, affording the desired amidation products
in moderate to good yields. Notably, both electron-rich anilines
and electron-deficient anilines were good substrates, resulting in
the desired products in 4585% isolated yields under same
conditions. This is quite different from the results reported in the

literature, which suggested that anilines containing electron-
withdrawing groups had lower reactivities than those containing
electron-donating groups.6 Highly hindered N,N,2,4,6-
pentamethylaniline provided the desired products in isolated
yields from 63% to 76% when the loading of itself increased
from 1.8 equiv to 2.0 equiv (relative to amides, entries 25 and
26). To the best of our knowledge, there has been no other report
describing the sp3 C-H bond amidation of such a sterically
hindered aniline. A 20% isolated yield of the amidation product
was obtained when a previously reported CuBr system was used
with N,N,2-trimethylaniline and acetamide as coupling partners.6
Aromatic amides containing electron-withdrawing groups
showed slightly higher reactivities than did those containing
electron-donating groups (entries 16). Pyridine-2-carboxamide,
pyrazine-2-carboxamide and furan-2-carboxamide were suitable
reactants, affording the desired products in 61%88% isolated
yields (entries 79). Heteroaromatic amides have seldom been
used as substrates in such amidation reactions.7a Aliphatic amides
(entries 1014, 1819, 22 and 23) and lactams (entries 1516,
20, 24 and 26) were also suitable substrates, the activities of
primary amides were higher than those of lactams. Phthalimide is
also active, however, a lower isolated yield of 45% was observed
(entry 17).24
5.
Zeng, H.-T.; Huang, J.-M. Org. Lett. 2015, 17, 42764279.
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Recently, Doyle and co-workers proposed
a
general
mechanism for transition metal-catalyzed N,N-dialkylaniline
oxidation using TBHP as the oxidatant; it involves a single
electron transfer (SET), followed by cleavage of the sp3 C–H
bond adjacent to the nitrogen atom to generate an iminium ion,
which is subsequently trapped by a nucleophilic reagent.25
Although further investigation is needed to clarify the detailed
mechanism of the present reaction, we suggest that the present
amidation reaction also proceeds via an electron transfer process,
similar to those reported previously.11-12 The general role of the
iron(III) species is to initiate conversion of TBHP to tert-
butylperoxy radicals, meanwhile imidazolium species may
accelerate the electron-transfer reaction.26
3. Conclusion
A novel, readily available, and easy-to-use ionic iron(III)
complex 2 was developed as an efficient and easy-to-use catalyst
for the amidation of unactivated sp3 C–H bonds of tertiary amines
by aromatic or aliphatic amides. All these reactions proceeded
under mild conditions, affording a wide range of amidation
products in moderate to good yields. The present work provides
an alternative practical protocol for C–N bond formation, and
shows the great potential of iron-based catalysts in direct sp3 C–
H bonds amidation reactions. Further investigations to extend
this method to other substrates and a detailed mechanistic study
are in progress.
24. The low isolated yield of desired product might be related to the poor
solubility of phthalimides in EtOAc. Under the same reaction conditions,
phthalimide provided a 50% yield of the desired product in CH3CN. It is
found that phthalimide can't be completely dissolved in CH3CN or
CH3OH under the reaction conditions, even if its solubility in CH3CN or
CH3OH is somewhat better than that in EtOAc.
Acknowledgements
25. Ratnikov, M. O.; Doyle, M. P. J. Am. Chem. Soc. 2013, 135, 15491557.
26. (a) Choi, D. S.; Kim, D. H.; Shin, U. S.; Deshmukh, R. R.; Lee, S.;
Song, C. E. Chem. Commun. 2007, 34673469; (b) Miao, C. X.; Wang,
J. Q.; Yu, B.; Cheng, W.-G.; Sun, J.; Chanfreau, S.; He, L.-N.; Zhang,
S.-G. Chem. Commun. 2011, 47, 26972699.
This project was supported by the National Natural Science
Foundation of China (Grant No. 21172164 and 21472134), the
Key Laboratory of Organic Chemistry of Jiangsu Province, and
the Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD).
Supplementary Material
References and notes
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Graphic abstract

Highlights



A novel ionic iron(III) complex has been prepared
Iron-catalyzed the direct sp3 C-H bonds amidation of N,N-dimethylanilines.
A new method for synthesis of N-substituted aromatic and aliphatic amides