C-H cycloamination of N-aryl-2-aminopyridines and N-arylamidines catalyzed by an in situ generated hypervalent iodine(iii) reagent

Article abstract of DOI:10.1039/c3cc43784a

A metal-free synthesis of diversified pyrido[1,2-a]benzimidazoles and 1H-benzo[d]imidazoles from N-aryl-2-aminopyridines and N-arylamidines has been developed. The C-H cycloamination reaction was catalyzed by hypervalent iodine(iii) species generated in situ from iodobenzene (catalytic) and peracetic acid (stoichiometric). The reaction proceeded smoothly at ambient temperature to provide the corresponding N-heterocycles in good to excellent yields.

Full text of DOI:10.1039/c3cc43784a

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C–H cycloamination of N-aryl-2-aminopyridines and
N-arylamidines catalyzed by an in situ generated
hypervalent iodine(III) reagent†
Cite this: Chem. Commun., 2013,
49, 7352
Received 20th May 2013,
Accepted 22nd June 2013
Yimiao He, Jinbo Huang, Dongdong Liang, Lanying Liu and Qiang Zhu*
DOI: 10.1039/c3cc43784a
www.rsc.org/chemcomm
A metal-free synthesis of diversified pyrido[1,2-a]benzimidazoles the construction of N-heterocycles.5 However, these reactions
and 1H-benzo[d]imidazoles from N-aryl-2-aminopyridines and are hard to scale up unless the hypervalent iodine reagents are
N-arylamidines has been developed. The C–H cycloamination reac- used in catalytic amounts.6 In this context, studies on in situ
tion was catalyzed by hypervalent iodine(III) species generated generated hypervalent iodine(III)-catalyzed C–C,7 C–O,8 and
in situ from iodobenzene (catalytic) and peracetic acid (stoichio- C–N9 bond-forming reactions grow rapidly. For example,
metric). The reaction proceeded smoothly at ambient temperature Antonchick et al. reported an efficient intramolecular C(sp2)–
to provide the corresponding N-heterocycles in good to excellent H amidation reaction using biaryliodide as a precatalyst in the
yields.
presence of peracetic acid as a stoichiometric oxidant at room
temperature.10 Herein, we report an in situ generated hyper-
Over the past decade, intramolecular C–N bond formation valent iodine(III)-catalyzed intramolecular C(sp2)–H amination
through direct C–H functionalization catalyzed by transition- of N-aryl-2-aminopyridines and N-arylamidines, providing effi-
metals such as Pd, Rh, Ru, and Cu complexes has emerged as a cient approaches to construction of diversified pyrido[1,2-a]-
step-efficient and atom-economic alternative to traditional benzimidazoles and 1H-benzo[d]imidazoles, respectively.
methods for the synthesis of N-heterocycles.1 However, these
The pyrido[1,2-a]benzimidazole scaffold exists in a wide
transition-metal-catalyzed reactions generally suffer from high range of biologically active compounds.11 Consequently, sub-
reaction temperature, narrow substrate scope, and the use stantial synthetic methods have been developed for the pre-
of stoichiometric or even excess amounts of metal salts as paration of this class of molecules. Conventional methods
oxidants.2 In large scale synthesis, these metal-based methods often suffer from lengthy synthetic routes, formation of regio-
are not only costly, but also problematic to remove heavy metal isomers, limited substrate scope, and/or unsatisfactory yields.12
contaminants from products. As a result, they are less applicable We and the group of Maes independently reported a novel
to drug synthesis especially at a late stage, despite their virtue of synthesis of pyrido[1,2-a]benzimidazoles through direct intra-
step-efficiency and atom-economy. Therefore, the development molecular C–H amination of N-aryl-2-aminopyridines catalyzed
of alternative metal-free (for both catalysts and oxidants) reac- by copper(II) in the presence of iron(III) and protic acid, respec-
tions that can be performed at ambient temperature starting tively.13,14 However, both of the approaches require high reac-
from unprefunctionalized precursors is highly desirable.
tion temperature (above 120 1C), and the substrate scope is
Recently, significant achievements have been made in limited in terms of substituents on the pyridine moiety.
hypervalent iodine(III)-mediated C–H amination, amidation, Inspired by recent advances in hypervalent iodine(III)-catalyzed
and imidation reactions under mild metal-free conditions.3 C–N formation,9 we envisioned that this metal-free strategy can
For instance, Chang et al. and DeBoef et al. reported elegant be applied to the synthesis of pyrido[1,2-a]benzimidazoles
research on PIDA-mediated intermolecular C–H imidation of starting from the same N-aryl-2-aminopyridines which are
both aryl sp2 and benzylic sp3 C–H bonds.4 Hypervalent readily available by coupling anilines with 2-bromopyridines.15
iodine(III)-promoted intramolecular oxidative C–N formation
The reaction conditions were optimized with N-phenyl-2-amino-
was also realized, and thus provided an efficient approach to pyridine 1a as a substrate in the presence of Bu4NI (10 mol%) and
TBHP (1.05 equiv.) in CH3CN at room temperature (entry 1,
Table 1). Unfortunately, no annulation product was detected. There
was no desired product formation either when the oxidants were
changed to H2O2 (30 vol% in water) in CH3CN or HFIP (entries 2
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
190 Kaiyuan Avenue, Guangzhou 510530, China. E-mail: zhu_qiang@gibh.ac.cn;
Fax: +86-20-3201-5299; Tel: +86-20-3201-5287
and 3). Gratifyingly, a combination of PhI (10 mol%) as an iodide
† Electronic supplementary information (ESI) available: General procedures,
spectral data and other supplementary information. See DOI: 10.1039/c3cc43784a source and m-CPBA (1.05 equiv.) as an oxidant in HFIP led to the
c
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Table 1 Optimization of the reaction conditionsa
With the optimal reaction conditions in hand, we next
examined the substrate scope for the synthesis of pyrido[1,2-a]-
benzimidazoles. As illustrated in Table 2, reactions of
N-aryl-2-aminopyridines bearing electron-donating (OMe, Me,
t-Bu) or electron-withdrawing (F, Cl, Br, NO2) groups at the para
position of the aniline moiety proceeded efficiently with good
to excellent yields (85–99%). However, when the same func-
tional groups (Me, F, NO2) were in the ortho position, the yields
were 9–23% lower than their para-substituted counterparts
(2l–2n), presumably due to the increased steric bulkiness. The
substrate with an iodo group was less compatible with the
current protocol, affording 2h in only 39% yield. To our delight,
when the reaction procedure was slightly modified by slow
addition of a solution of peracetic acid (34 mL) in HFIP (1.0 mL)
for 5 minutes to a HFIP (1.0 mL) solution of N-(4-iodophenyl)-2-
aminopyridine, the yield of 2h was improved significantly to
91%. It was notable that acetylene functionality also survived
the oxidative conditions (2i). Unfortunately, a mixture of 1 : 1
regioisomers 2k and 2k0 was obtained for meta-substituted
substrates. The scope of substituents on the pyridine ring was
then investigated. Substrates with Me, F, Cl, CO2Et, or CF3 on
the pyridine moiety reacted smoothly to furnish the corre-
sponding products (2o–2u) in good yields (67–97%). In addi-
tion, quinoline and isoquinoline derived substrates were also
compatible with the reaction conditions (2v–2w).
Entry
Precat.
Oxidant
TBHPc
Solvent
Yieldb (%)
1
2
3
4
5
6
7
Bu4NI
Bu4NI
Bu4NI
PhI
PhI
PhI
CH3CN
CH3CN
HFIP
HFIP
HFIP
n.r.
n.r.
n.r.
n.r.
n.r.
66
d
H2O2
TBHPc
d
H2O2
TBHPc
m-CPBA
HFIP
HFIP
PhI
CH3CO3He
91
a
Reaction conditions: 1a (0.2 mmol), precatalyst (10 mol%), oxidant
(0.21 mmol, 1.05 equiv.) in solvent (2 mL) at 25 1C for 1.5 h; TBHP =
tert-butyl hydroperoxide, HFIP
= 1,1,1,3,3,3-hexafluoro-2-propanol,
b
m-CPBA = m-chloroperbenzoic acid, n.r. = no reaction. Isolated yields
c
d
e
of 2a. 70 vol% in water. 30 vol% in water. 43 wt% in HOAc.
formation of pyrido[1,2-a]benzimidazole 2a in 66% yield (entry 6).
Switching the oxidant to peracetic acid improved the yield of 2a
significantly to 91%. It was notable that the high-yield formation of
2a was realized at ambient temperature in only 1.5 h in the absence
of any metal catalysts or oxidants. Although 2a could be obtained
from 1a in a comparable yield of 88% by following our previous
method,13 high loading of the copper catalyst (50 mol% of
Cu(OAc)2 together with 10 mol% of Fe(NO3)3ꢀ9H2O) under much
harsher conditions (5 equivalents of PivOH, 130 1C, 28 h) was
required.
N-Phenylbenzamidine derivatives 3 were also applicable to the
oxidative cycloamination process (Table 3).9d Both electron-rich and
electron-poor N-phenylbenzamidines afforded the corresponding
2-phenyl-1H-benzo[d]imidazoles 4a–4d in good yields at slightly
elevated temperature (50 1C). This catalytic method provides a
complementary approach to the synthesis of benzo[d]imidazoles,
a class of N-heterocycles with broad bioactivities.16
Table 2 Synthesis of derivatives of pyrido[1,2-a]benzimidazolesa
The scalability of the method was verified by running
the reaction of 1a on both 3 and 10 mmol scales (Scheme 1).
Table 3 Synthesis of 2-phenyl-1H-benzo[d]imidazolesa
a
Reaction conditions:
3 (0.2 mmol), PhI (10 mol%), CH3CO3H
(1.05 equiv.) in HFIP at 50 1C, 1.5 h, isolated yields of 4.
a
Reaction conditions: 1 (0.2 mmol), PhI (3 mL, 10 mol%), CH3CO3H
b
(34 mL, 1.05 equiv.) in HFIP at 25 1C, isolated yields of 2. Dropwise
addition of a solution of peracetic acid (34 mL) in HFIP (1.0 mL) for
5 min to a HFIP (1.0 mL) solution of N-(4-iodophenyl)-2-aminopyridine
at 25 1C.
Scheme 1 Large scale synthesis of 2a.
c
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Based on literature reports,9,10 a plausible reaction pathway
was proposed as in Scheme 2. Initially, iodobenzene is oxidized
by peracetic acid, forming phenyliodine diacetate (PIDA) in the
presence of acetic acid. Then, nucleophilic substitution of the
aniline nitrogen on the iodine(III) center in PIDA forms inter-
mediate A which contains an electrophilic N-iodo moiety.
Subsequent nucleophilic attack of the pyridine nitrogen on
the aniline ring gives the intermediate B with concurrent
release of PhI and AcO–. Finally, deprotonic rearomatization
furnishes the desired product 2a, generating acetic acid and
water as only by-products during the whole process. The
released PhI enters the catalytic cycle again upon reoxidation
by peracetic acid acting as a stoichiometric oxidant.
In summary, we have developed a metal-free synthesis of
pyrido[1,2-a]benzimidazoles and benzo[d]imidazoles with high
step-efficiency and atom-economy. The reaction is catalyzed by
hypervalent iodine(III) species generated in situ from catalytic
amounts of PhI and peracetic acid which is used as a stoichio-
metric oxidant. The cycloamination reaction proceeded smoothly
at relatively low temperature within short reaction time (1.5 h). A
variety of functional groups are compatible with the reaction
conditions, providing the corresponding diversified N-hetero-
cycles in good to excellent yields. The pyrido[1,2-a]benzimidazole
derivatives with electron-withdrawing groups on the pyridine
moiety are inaccessible by similar Cu-catalyzed C–H cycloamina-
tion approaches.13,14 The features of scalability and free of metals
make this approach potentially valuable in drug synthesis.
We are grateful to the National Science Foundation of China
(21272233, 21202167 and 21072190) for financial support of
this work.
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