Regioselective C-H Amidation of (Alkyl)arenes by Iron(II) Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b00697

A nondirected amidation reaction of aromatic C-H bond was developed under iron(II) catalysis, using sulfonyl azides as the nitrogen source. The reaction displayed a broad substrate scope and good regioselectivities in the aspects of aromatic ring vs alkyl

Full text of DOI:10.1021/acs.orglett.9b00697

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective C−H Amidation of (Alkyl)arenes by Iron(II) Catalysis
Yao Ding,† Shen-Yuan Zhang,† Yu-Chen Chen,‡ Shuai-Xin Fan,† Jie-Sheng Tian,*,†
and Teck-Peng Loh*,†,‡,§
†Institute of Advanced Synthesis (IAS), School of Chemistry and Molecular Engineering (SCME), Jiangsu National Synergetic
Innovation Center for Advanced Materials (SICAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing
211816, P. R. China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
§Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
ABSTRACT: A nondirected amidation reaction of aromatic
C−H bond was developed under iron(II) catalysis, using
sulfonyl azides as the nitrogen source. The reaction displayed
a broad substrate scope and good regioselectivities in the
aspects of aromatic ring vs alkyl chain and different aromatic
position of (alkyl)arenes. This method provided a new
protocol for the synthesis of some aromatic amines, which
were hard to achieve in a previous report.
ortho position (Figure 1). On the other hand, in recent
years, iron-catalyzed intramolecular C−H bond amination for
irect C−H bond amination/amidation of aromatic
Dmolecules has been one of the most promising research
topics in organic synthesis due to the amino functional groups
on the aromatic rings widely existing in a variety of natural
products, pharmaceuticals, or functional materials.1,2 This
method provides the convenience for simplifying the synthetic
routes and diversifying complex molecules through directly
introducing an amino functionality into the aromatic rings.
Recently, two general strategies were presented on the basis of
a selection of a nitrogen source in (i) amines or amides with
external oxidants or (ii) preactivated nitrogen-containing
compounds readily cleavaged by N−X bonds, such as N-
chloroamines, N-hydroxycarbamates, O-acylhydroxylamines,
nitrosobenzenes, and NFSI.3,4 Among these reported ap-
proaches, organic azides are regarded as the environmentally
benign nitrogen source and were extensively utilized for the
direct amination/amidation of aromatic C−H bonds.5 In this
context, great progress has been made since Chang and co-
workers successfully demonstrated and extended it through
chelation-assisted C−H activation.6 Accordingly, some repre-
sentative examples were reported including Glorius and co-
workers’ Rh(III)/Cu(II)-cocatalyzed synthesis of 1H-inda-
zoles,7 the groups of Ackermann8 and Jiao’s9 Ru-based
catalytic systems, Kanai group’s directed C(sp2)−H amidation
of indoles catalyzed by Cp*Co,10 Zhu group’s Cu-based
Figure 1. C−H amidation strategy.
the synthesis of N-heterocycles was also studied by preparing
complex organic azides as the starting materials.14
Therefore, it is very desirable to explore cheaper and more
efficient catalytic systems for direct C−H bond amidation of
aromatic molecules by employing organic azides as a nitrogen
source especially in the absence of directing groups. Our
interest lies in the development of inexpensive, simple iron salt
catalytic systems for the exploration of: (i) the selective
C(sp2)−H bond amidation of (alkyl)arenes and (ii) the
regioselective C−H bond amidation of aromatic rings through
electronic effect and steric control using sulfonyl azides as the
environmentally benign nitrogen source (Figure 1). We herein
report a method for the amidation of an aromatic C−H bond
under iron catalysis using organic azides as the aminating
catalytic systems,11 and Konig and co-workers’ visible-light C−
̈
H amidation of heteroarenes.12 Additionally, our group also
successfully expanded C−H amidation of cyclic N-sulfonyl
ketimines by iridium(III) catalysis.13 However, in most of
these processes, the assistance of the directing groups and the
catalysis of expensive transition metal are necessary for
achieving C(sp2)−H bond amination/amidation at their
Received: February 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00697
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
agents. The reaction displayed a broad substrate scope and
good regioselectivities in the aspects of aromatic ring vs alkyl
group and different aromatic position of (alkyl)arenes under
the influence of electronic effect and steric hindrance.
(Table 1, entries 11 and 12). Therefore, the optimized reaction
conditions are as follows: the reaction was performed using 20
mol % of FeBr2, sulfonyl azide and 4.0 equiv of (alkyl)arene in
dichloroethane at 100 °C.
Next, the scope and steric effect of structurally varied
sulfonyl azides on the regioselective C−H bond amidation of
m-xylene were investigated through adjusting the substituents
of sulfonyl azides (Scheme 1). Moderate to good yields of the
To explore the possibility of C(sp2)−H bond amidation of
(alkyl)arenes and assess the selectivity of sp2 vs sp3 C−H bond
functionalization, an initial study was conducted by employing
m-xylene 1a with 4-nitrobenzenesulfonazide (NsN3) 2a as the
nitrogen source in the presence of iron(II) chloride.
Interestingly, the product 3a of C(sp2)−H bond amidation
was obtained in 70% isolated yield with an NMR ratio of 29:71
(b:d) (Table 1, entry 2). Furthermore, no multiamidation
Scheme 1. Effect of Structurally Varied Sulfonyl Azides on
a b
,
the Regioselective Amidation of m-Xylene
a b
,
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
t (h)
yield (%)
ratio (b:d)
1
2
3
4
5
6
−
FeCl2
Fe(OAc)2
Fe(OTf)2
Fe(acac)3
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
72
72
72
72
72
48
48
72
72
48
72
72
0
−
70
18
12
7
75
49
66
33
48
0
29:71
25:75
23:77
27:73
25:75
25:75
28:72
26:74
27:73
−
d
7
e
8
f
9
g
10
11
12
h
FeBr2
FeBr2
i
trace
−
a
Unless otherwise noted, the reactions were carried out at 100 °C
using 1a (1.00 mmol), 2a (0.25 mmol), Fe salts (20 mol %), and
b
c
DCE (1.0 mL), in N2 atmosphere. Isolated yields. 1H NMR ratio.
a
d
e
f
Unless otherwise noted, the reactions were carried out using 1a
(1.00 mmol), 2 (0.25 mmol), FeBr2 (0.05 mmol, 20 mol %), and
80 °C. The molar ratio of 1a and 2a (3:1). The molar ratio of 1a
g
h
i
and 2a (1:1.5). 10 mol % FeBr2. MeCN. 1,4-Dioxane.
b
DCE (1.0 mL), in N2, at 100 °C. Isolated yields.
product was detected. As shown in Table 1 (entries 3−6),
other iron salts were also screened for this reaction. The
desired product could be acquired in low yields (18%, 12%,
and 7%) when Fe(OAc)2, Fe(OTf)2, and Fe(acac)3 were used
as the catalyst, respectively. To our delight, the use of FeBr2
(20 mol %) as the catalyst was examined for this reaction at
100 °C for 48 h, leading to 75% yield with good
regioselectivity (b:d = 25:75) in the different position of m-
xylene 1a (Table 1, entry 6). It is noteworthy that no
amidation product was given in the absence of the iron catalyst
(Table 1, entry 1). When the reaction temperature was
decreased to 80 °C, only a moderate amount of desired
product was obtained (Table 1, entry 6 vs 7). To inquire into
the optimum molar ratio of m-xylene 1a and NsN3 2a used in
the reaction, several control experiments were carried out by
varying the different molar ratio. The results showed that 4.0
equiv of m-xylene 1a to 2a was most effective for this reaction
(Table 1, entries 6, 8, and 9). We also observed a significant
reduction of the catalytic efficiency with changing the catalytic
quantity to 10 mol % (Table 1, entry 10). Various solvents
were then tested for this reaction, but only DCE provided
good yield, and no or a trace amount of the desired product
was given if MeCN or 1,4-dioxane was used as the solvent
amidation products 3a−i were provided with few exceptions.
4-Nitrobenzenesulfonyl azide 2a is the suitable nitrogen source
for this reaction, affording the desired product 3a in 75% yield
with good positional selectivity. The reaction reactivities
obviously decreased if an electron-withdrawing group was
added in the 2 or 3 position of the azide 2a (compare 2b and
2c with 2a). When the azide 2d with a bulky tert-butyl group
instead of a nitro one was used for this reaction, the slight
lessening was observed in the amidation regioselectivity.
Gratifyingly, the introduction of a congested methyl group at
the ortho position such as sulfonyl azides 2e and 2f could
increase the positional selectivity of the aromatic amidation.
However, the use of other sulfonazides such as 2g, 2h, and 2i
could not augment the regioselectivity as presented in Scheme
1. Perhaps the joint influence of electronic factor and steric
hindrance led to a subtle equilibrium, thus determining the
relative rate and associated regioselectivity. Therefore, on
considering the efficiency and selectivity of the reaction, NsN3
was chosen to be our model amidation reagent for further
investigation.
After the identification of the standard reaction conditions,
we turned our attention to explore the scope of various
B
DOI: 10.1021/acs.orglett.9b00697
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
aromatic molecules for C(sp2)−H bond amidation. As shown
Furthermore, diphenyl ether 1i can react with NsN3 to furnish
the regiospecific product at the 4-position. If anisole derivatives
1j−k and 1m,n containing a para substituent such as methyl,
ethyl, Br, or F were used, the amidation selectively occurred at
the more electron-rich ortho site. The result comparison
between 1g and 1p also confirmed the inconsistency with
Friedel−Crafts pattern.
in Scheme 2, a broad range of simple (alkyl)arenes, aryl
a b
,
Scheme 2. Examination of Arene Scope
Subsequently, the application of aromatic C−H bond
amidation to the modification of biologically complex
molecules is explored as well. α-Tocopherol derivative 1q
was selected as the typical representative. It is gratifying that
the desired product 3y was obtained in good yields at 80 °C
for 48 h (Scheme 3).
Scheme 3. Aromatic C−H Amidation of α-Tocopherol
Derivative 1q
Addition of TEMPO significantly inhibited the reaction,
which indicated that radicals might be involved in the C−N
bond formation. On the basis of the experimental results and
literature reports,14 two possible reaction pathways were
proposed as presented in Scheme 4. First, the interaction of
iron(II) bromide with NsN3 formed the Fe(III) radical imido
intermediate. Next, this active species reacted with arene via
(1) H atom abstraction, then radical rebound to the Fe(III)
amide, or (2) C−N bonding, then H atom abstraction rebound
to Fe(III) amide, thus leading to the formation of an amidation
a
Unless otherwise noted, the reactions were carried out using 1 (1.00
mmol), 2a (0.25 mmol), FeBr2 (0.05 mmol, 20 mol %), and DCE
Scheme 4. Plausible Reaction Mechanism
b
(1.0 mL), in N2, at 100 °C. Isolated yields based on 4-
nitrobenzenesulfonazide 2a.
halides, and anisole derivatives could be transformed smoothly
into the expected products in moderate to good yields (43%−
89%) under the catalysis of cheap iron(II) bromide. For the
aromatic ring containing alkyl substituents 1a−d, 1g−h, and
1j−k, the amidation of the aromatic C−H bond is
preferentially occurring in comparison to the benzylic C−H
bond. Benzene 1e and naphthalene 1f as the most simple arene
and polycyclic arene were also the suitable substrates for this
reaction. In view of the low boiling point of benzene, the
reaction was performed with no additional solvent (DCE).
Encouraged by these results, an array of the functionized
aromatic molecules with halides 1g−h and 1m−p and ether
functional moieties 1i−p were explored. The observation on
the aminating regioselectivity of the simple substrates with
different aromatic C−H bonds is consistent with the regular
pattern of Friedel−Crafts reaction, whereas if a multi-
substituted aromatic molecule was subjected to the standard
reaction conditions, the aminating product at the unpredicted
position can be obtained under the combined influence of
electronic effect and steric hindrance. Aryl bromides 1g−h and
ethers 1i−p were compatible with the catalytic system.
C
DOI: 10.1021/acs.orglett.9b00697
Org. Lett. XXXX, XXX, XXX−XXX

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product. Of course, up to now we still have no more evidence
to support which mechanism this reaction undergoes.
In conclusion, we have developed an iron-catalyzed reaction
for the conversion of an aromatic C−H to C−N bond with
sulfonyl azides as the aminating source in the absence of a
directing group. The reaction displayed the broad substrate
scope and good regioselectivities in two aspects of (i) aromatic
ring vs alkyl group and (ii) different aromatic position of
(alkyl)arenes. This method provided a new protocol for the
synthesis of some aromatic amines, which are hard to achieve
in a previous report. In addition, a plausible reaction
mechanism was proposed. The exploration of a new catalytic
system to increase the regioselectivity, further application to
the synthesis of biologically active complex molecules, and
detailed mechanism studies are currently underway in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00697.
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Synthetic procedures, mechanistic studies, and NMR
data (PDF)
(10) (a) Sun, B.; Yoshino, T.; Matsunaga, S.; Kanai, M. Adv. Synth.
Catal. 2014, 356, 1491. (b) Sun, B.; Yoshino, T.; Matsunaga, S.;
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(11) Peng, J.; Xie, Z.; Chen, M.; Wang, J.; Zhu, Q. Org. Lett. 2014,
16, 4702.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ias_jstian@njtech.edu.cn.
*E-mail: teckpeng@ntu.edu.sg.
ORCID
̈
(12) Brachet, E.; Ghosh, T.; Ghosh, I.; Konig, B. Chem. Sci. 2015, 6,
987.
Teck-Peng Loh: 0000-0002-2936-337X
Notes
(13) Maraswami, M.; Chen, G.; Loh, T.-P. Adv. Synth. Catal. 2018,
360, 416.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Nanjing Tech University, Natural
Science Foundation of Jiangsu Province (BK20171463), the
State Key Program of National Natural Science Foundation of
China (21432009), students’ project of Nanjing Tech
University for innovation and entrepreneurship training
program (2019DC0428), SICAM Fellowship and Scholarship
by Jiangsu National Synergetic Innovation Center for
Advanced Materials, and Nanyang Technological University
for the generous financial support.
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DOI: 10.1021/acs.orglett.9b00697
Org. Lett. XXXX, XXX, XXX−XXX