Hypervalent iodine mediated oxidative radical amination of heteroarenes under metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2017.06.081

A metal-free, PhI(OCOCF₃)₂-mediated C[sbnd]N bond forming reaction was developed between quinolines and nitrogen source, affording a facile route for the construction of 2-aminoquinolines via a nitrogen-centered radical process. This reaction represents a significant addition to the limited number of existing transition metal-catalyzed processes for the C-2 amination of quinolines and will find practical application in the synthesis of nitrogen-functionalized quinolines.

Full text of DOI:10.1016/j.tetlet.2017.06.081

ꢀꢁꢁꢂꢃꢄꢂꢅꢆ ꢇꢈꢉꢊꢁꢋꢌꢃꢄ

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A radical-type amination process for the
facile synthesis of 2-aminoheterarenes has
Hypervalent Iodine Mediated Oxidative
Radical Amination of Heteroarenes under
Metal-free Conditions
Feng Zhao, Ting Sun, Hefeng Sun, Gaolei Xi and Kai Sun

1
Tetrahedron Letters
Hypervalent Iodine Mediated Oxidative Radical Amination of Heteroarenes under
Metal-free Conditions
Feng Zhao a, b , Ting Sun a , Hefeng Sun c , Gaolei Xi d and Kai Sun a, b,
a College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455000, P. R. China
b Henan Province Key Laboratory of New Opto-Electronic Functional Materials, Anyang 455000, P. R. China
c The Ping Mei Senior High School, Chifeng, Inner Mongolia Autonomous Region, 024076, P. R. China
d Technology Center，China Tobacco Henan Industrial Co.，Ltd.，Zhengzhou 450000，P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A metal-free, PhI(OCOCF3)2-mediated C–N bond forming reaction was developed
between quinolines and nitrogen source, affording a facile route for the construction of 2-
aminoquinolines via a nitrogen-centered radical process. This reaction represents a
significant addition to the limited number of existing transition metal-catalyzed processes
for the C-2 amination of quinolines and will find practical application in the synthesis of
nitrogen-functionalized quinolines.
Available online
Keywords:
Heteroarenes ;
Amination;
2009 Elsevier Ltd. All rights reserved.
Radical;
C–N bond;
Metal-free conditions
1. Introduction
The development of new reactions for the amination of
(hetero)arenes represents an important area of research because
the resulting nitrogen-containing molecules are of considerable
interest to the synthetic, biological, and medicinal sciences.1
Compared with the well-established nucleophilic and
electrophilic amination reactions, the synthetic potential of
procedures based on nitrogen-centered radicals remains largely
unexplored, despite the important roles played by nitrogen-
centered radicals in many chemical and biological processes.2
Considering the importance of quinolines and their derivatives in
medicinal and materials chemistry,3 the derivatization of
quinolines has attracted considerable interest from synthetic
chemistry in recent years, culminating in several transition metal-
catalyzed reactions for the regioselective C−H amination of
quinolines.4 However, the application of these processes has been
limited by their requirement for extensive purification processes
to remove residual catalysts from the product stream, especially
in the pharmaceutical industry. The development of alternative
procedures for the organocatalyst-mediated amination of
quinolines is therefore strongly desired to provide sustainable
approaches for the introduction of nitrogen functional groups.
Several organocatalyst-mediated, radical-type functionalization
reactions involving quinolines have been reported to date,
Scheme 1. C-2 amination of quinolines.
there have not been reports describing the highly regioselective
radical-type amination of quinolines in this way, which could be
attributed to the lack of relatively stable circumstantial factors
and the availability of a convenient route for the generation of
nitrogen-centered radicals.
Hypervalent iodine compounds are widely used in organic
synthesis as selective oxidants and environmentally friendly
reagents.6 Hypervalent iodine reagent mediated C2-
functionalization,7 including the nitrogen radical-type amination
including azidation and hosphorylation reactions.5 However,
———
 Corresponding author. Tel.: +86-372-2900040; e-mail: sunk468@nenu.edu.cn

2
Tetrahedron Letters
Table 1. Optimization of the reaction conditionsa
quinoline to give the desired product 3a, albeit in a low yield, in
the presence of PhI(OCOCF3)2 (Table 1, entry 2). Several other
hypervalent iodine reagents, including 1-fluoro-3,3-dimethyl-1,3-
dihydro-λ3-benzo[d][1,2]iodoxole I (Togni reagent-I) and 1-
trifluoromethyl-1,2- benziodoxol-3(1H)-one II (Togni reagent-
II) were also tested, but failed to afford any of the desired
product 3a (Table 1, entries 3 and 4). A variety of different
solvents were also screened against the reaction, and the results
revealed that polar solvents appeared to facilitate the coupling
procedure (Table 1, entries 5−10). Among the solvents examined
(CH3CN, THF, CH3NO2, EtOAc, chlorobenzene, DCE, and
cyclohexane), EtOAc gave the best results, affording 3a in 73%
yield (Table 1, entry 7). THF also performed well in this reaction
(Table 1, entry 5). Gratifyingly, the yield was increased to 79%
when the temperature was decreased to 60 °C (Table 1, entries
11−13). The amount of PhI(OCOCF3)2 was also found to be
important for improving the reaction efficiency (Table 1, entry
14). After surveying a variety of oxidants, solvents, and
temperatures, we found that the combination of 2 eq. of
PhI(OCOCF3)2 in EtOAc at 60 °C gave the optimal conditions
for this transformation. These results highlight the attractive
features of this facile transformation, in that it does not require
pre-activated substrates, the addition of a metal catalyst or ligand,
or high-temperature conditions.
With the optimized conditions in hand, we proceeded to
investigate the scope of this reaction using a variety of different
quinolines 1 and saccharin 2a (Table 2). Notably, the positioning
of the substituent on the quinoline ring had no discernible impact
on the reaction efficiency. For example, quinoline substrates
bearing a 3-methyl, 4-methyl, 5-bromo, 6-methoxy, or 8-methyl
substituent all reacted smoothly with saccharin 2a to give the
corresponding addition products in good yields (3b−3i, Table 2).
Various other functional groups that are commonly used in
synthetic chemistry were also found to be compatible with the
optimized reaction conditions, including halogen (1g, 1h, 1k),
thereby significantly expanding the synthetic utility of this newly
developed C–N bond forming protocol. Isoquinoline 1m,
quinoxaline 1n and quinazoline 1o also reacted efficiently under
the optimized reaction conditions to give the corresponding
addition products in high yields (3m−3o, Table 2). 1H-
benzotriazoles can be found in a wide range of compounds
Entry
1
Oxidant
Additive
CH3CN
CH3CN
CH3CN
CH3CN
THF
Temp (°C) Yield (%)b
PhI(OAc)2
90
90
90
90
90
90
90
90
90
90
60
40
20
60
0
34
2
PhI(OCOCF3)2
Togni reagent-I
Togni reagent-II
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
3
0
4
0
5
51
6
CH3NO2
EtOAc
27
7
73
8
chlorobenzene
DCE
< 10
< 10
< 10
79
9
10
11
12
13
cyclohexane
EtOAc
EtOAc
71
EtOAc
60
14
EtOAc
48c
a
Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol) and oxidant (1.0
mmol) in solvent (3 mL) under air for 8 h. b Yield of isolated product. c 1 eq.
PhI(OCOCF3)2 was added.
of C(sp2)–H bonds have also been exploited for several specific
substrates. The functionalization of quinoline-type substrates
with metal-based catalytic systems represents a challenging
transformation because of the strong coordinating ability of these
systems and their electron-deficient nature. It was therefore
envisaged that hypervalent iodine regents could be ideal non-
metallic promoters for the radical-type amination of quinolines
because of their ability to avoid the issues associated with metal
coordination
and
contamination.
Indeed,
heterocyclic
exhibiting
interesting
biological
properties,
including
compounds, such as quinolines, pyrroles, and even thiophenes,
are ideal acceptors for nitrogen-centered radicals.8 The addition
of a nitrogen-centered radical to a heteroarene would generate a
C−N bond and a carbon-centered radical, which would be
oxidized to a carbocation followed by deprotonation to
regenerate an aromatic ring. Zhang et al. recently achieved the
highly regioselective aminocyanation, diamination, and
aminofluorination of alkenes via the addition of nitrogen-
centered radicals to unsaturated bonds, as well as a radical-based
cascade reaction between alkynes, sulfonamides, and alcohols.9
As part of our ongoing interest in the development of new
methods for the formation of C–N bonds,10 we herein disclose
our latest work on the hypervalent iodine regent-mediated
regioselective C2 amination of various heterocyclic compounds
using nitrogen-centered radicals (Scheme 1).
antibacterial, anticancer, antidepressant, antifungal, and
antimalarial activities. This motif also represents a useful synthon
for the Graebe–Ullmann reaction, especially for the synthesis of
pyridoacridines,
carbolines,
and
tetraazapentalenes.11
Benzimidazole drugs represent a large family of compounds,
including benzimidazole anthelmintics, which are broad-
spectrum drugs that are widely used for the prevention and
treatment of endoparasites in food-producing animals.12 To
expand the synthetic utility of our newly discovered nitrogen-
centered radical amination reaction, we investigation the
performances of 1H-benzotriazole, and benzimidazole under the
optimized conditions. Pleasingly, these substrates all reacted
smoothly to give the desired products in high yields (3p and 3q,
Table 2).
2. Results and discussion
Inspired by these results, we investigated the application of our
new strategy to the regioselective C2 amination of other
nitrogen-centered radical acceptor such as pyridine 1r and
pyrrole 1s, (Table 2). Pleasingly, the amidation proceeded smoot
hly and furnished the desired products 3r–3t, with the addition
occurring exclusively at the C2 position. Recently, Kita et al.
reported the N1-selective oxidative C–N coupling of azoles with
We commenced our study by examining the reaction of
quinoline 1a with saccharin 2a under various catalytic conditions
(Table 1). We found that PhI(OAc)2 failed to mediate the desired
C–N bond forming reaction in acetonitrile at 90 °C, with 1a
being recovered unchanged after 8 h (Table 1, entry 1).
Pleasingly, saccharin 2a was incorporated at the C2 position of

3
Table 2. Scope of the heterocycles and amino componentsa,b
Scheme 3 Reactions determining the mechanism.
BHT led to the formation of the coupling product H via the
reaction of BHT with the supposed nitrogen-centered radical B in
34% yield. These experimental results therefore supported the
occurrence of a radial mechanism and involving nitrogen-
centered radicals. We also prepared the nitrogen-iodo (III)
species A according to a reported procedure.14 The direct reaction
of A with quinoline 1a afforded 3a in 23% yield (Scheme 3c).
This result implied that A could be an active intermediate in the
current amination reaction. When benzene was introduced under
the standard conditions, we did not observe a C–N bond forming
reaction, as expected (Scheme 3d). We therefore reasoned that
the key to the success of this reaction was the positive role played
by the heteroatom in stabilizing the radical intermediates.
a
Reaction conditions: 1 (0.5 mmol), 2 (0.55 mmol) and PhI(OCOCF3)2 (1.0
mmol) in EtOAc (3 mL) at 60 °C for 8 h. b Yield of isolated product.
pyrroles and indoles.13 Notably, Kita’s reaction conditions failed
to achieve the C–N coupling of an azole to a quinoline or
pyridine, further highlighting the broad scope of our work.
To demonstrate the synthetic utility of this amidation protocol,
the reaction of deprotection of saccharin moiety was conducted
and high yield of quinolin-2-amine was obtained according to
previous work. (Scheme 2).
Scheme 4 Proposed reaction mechanism.
Based on these findings, we have proposed a catalytic cycle
involving nitrogen-centered radical species (Scheme 4). An
initial ligand exchange between PIFA and saccharin (2a) would
afford the nitrogen-iodine(III) species A, which would undergo a
thermal hemolytic cleavage step to generate the nitrogen-
centered radical B. The addition of this nitrogen-centered radical
to quinoline 1 would afford the nitrogen-centered radical C (or
the allyl radical species D). Subsequently H-abstraction process
from C by the remanent nitrogen-centered radical B would
deliver the desired aminated product 3. However, the exclusive
C2 selectivity is in conflict with the radical mechanism, therefore,
another plausible pathway through the direct activation of
quinolines by PIFA, then followed by nitrogen attack through the
intramolecular or intermolecular fashion can not be excluded.
Scheme 2 Application study.
Several control experiments were conducted to develop an
insight into the mechanism of this reaction (Scheme 3). When 1a
was reacted with 2a under the optimized conditions in the
presence of 1 eq. of the radical scavenger 2,2,6,6-tetramethyl-1-
piperi-dinyloxyl (TEMPO), the yield of 3a fell to 17% (Scheme
3a). Moreover, the addition of 1 eq. of 2,6-di-tert-butyl-4-
methylphenol (BHT) completely inhibited the reaction, with none
of the desired product 3a being detected even after an extended
reaction time (Scheme 3b). Notably, however, the addition of

4
Tetrahedron Letters
3. Conclusion
excellent functional group compatibility, this radical procedure
should find practical application in the synthesis of nitrogen-
containing molecules, especially in the pharmaceutical industry.
Detailed studies aimed at elucidating the mechanism of this
process are currently underway in our laboratory.
In conclusion, a facile PhI(OCOCF3)2-mediated methodology
has been developed for the formation of nitrogen-centered
radicals from various N–H-containing compounds. This reaction
allowed for the facile preparation of a wide variety of 2-
aminoheterarenes via a radical-type amination process. Taking
into account its many desirable features, including mild
conditions, operational simplicity, broad substrate scope, and
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (U1504210); Jilin Province Key Laboratory of Organic
Functional Molecular Design
aynu201710 and AYNU-KP-B06 for financial support of this
research.
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5
Highlights
A metal-free method is developed for the formation
of N-containing heterocycles.
A radical-type amination process is proposed to
explain the mechanism.
The features include mild conditions and broad
substrate scope.

6
Tetrahedron