A direct intramolecular C-H amination reaction cocatalyzed by copper(II) and iron(III) as part of an efficient route for the synthesis of pyrido[1,2-a ]benzimidazoles from N-aryl-2-aminopyridines

Article abstract of DOI:10.1021/ja1067993

A novel and efficient synthesis of pyrido[1,2-a]benzimidazoles through direct intramolecular aromatic C-H amination of N-aryl-2-aminopyridines has been developed. The reaction, cocatalyzed by Cu(OAc)₂ and Fe(NO ₃)₃?9H

Full text of DOI:10.1021/ja1067993

Published on Web 09/07/2010
A Direct Intramolecular C-H Amination Reaction Cocatalyzed by Copper(II)
and Iron(III) as Part of an Efficient Route for the Synthesis of
Pyrido[1,2-a]benzimidazoles from N-Aryl-2-aminopyridines
Honggen Wang, Yong Wang, Changlan Peng, Jiancun Zhang,* and Qiang Zhu*
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of
Sciences, 190 Kaiyuan AVenue, Guangzhou 510530, China
Received July 30, 2010; E-mail: zhu_qiang@gibh.ac.cn
functionality tolerance is highly desirable. To this end, we reasoned
Abstract: A novel and efficient synthesis of pyrido[1,2-a]benz-
that the pyrido[1,2-a]benzimidazole nucleus could be constructed
imidazoles through direct intramolecular aromatic C-H amination
by direct intramolecular C-H amination reactions of readily
of N-aryl-2-aminopyridines has been developed. The reaction,
available N-aryl-2-aminopyridines (Scheme 1), in which the pyridine
cocatalyzed by Cu(OAc)2 and Fe(NO3)3 ·9H2O, is carried out in
DMF under a dioxygen atmosphere. Diversified pyrido[1,2-
a]benzimidazoles containing various substitution patterns are
moiety serves as a directing group as well as an intramolecular
nucleophile.
obtained in moderate to excellent yields by using this procedure.
Scheme 1. Intramolecular C-H Activation/C-N Bond Formation
The results of mechanistic studies suggest that a Cu(III)-catalyzed
electrophilic aromatic substitution (SEAr) pathway is operating in
this process. The unique role of iron(III) is believed to lie in its
ability to facilitate formation of the more electrophilic Cu(III)
species. In the absence of iron(III), a much less efficient and
reversible Cu(II)-mediated SEAr process takes place.
Direct C-H functionalization processes that feature atom
economy and high bond-formation efficiencies have received
substantial attention in recent years.1 Compared with traditional
To test this hypothesis, a study of the reaction of N-phenyl-2-
aminopyridine 1a under Buchwald’s carbazole synthesis conditions
was conducted.4a Unfortunately, none of the expected product 2a
was formed in the reaction in toluene. However, conversion of 1a
to 2a did take place when DMF was employed as the solvent (47%;
Table 1, entries 1-2). A further investigation of the process revealed
that the palladium catalyst was not needed since substoichiometric
amounts of Cu(OAc)2 alone catalyze the reaction with almost the
same efficiency seen when the palladium catalyst was present (Table
1, entry 3). Moreover, the yield of 2a increased to 81% when 10
mol % of iron salts were included in the reaction mixture, with
Fe(NO3)3 ·9H2O being the most effective (Table 1, entries 4-6).
Control experiments showed that iron salts themselves did not
promote the reaction.16 The yield of 2a was further improved to
88% (Table 1, entry 7) when pivalic acid was utilized as an
additive,17 albeit an extended reaction time was required for
complete consumption of 1a. The amount of Cu(OAc)2 employed
to promote this reaction can be reduced to 20 mol % without a
significant loss of yield with the requirement of longer reaction
times (Table 1, entry 8).
Conditions involving 20 mol % of Cu(OAc)2, 10 mol % of
Fe(NO3)3 ·9H2O, and 5.0 equiv of pivalic acid in DMF under a
balloon pressure of O2 at 130 °C were selected to explore the
generality of this novel method for the synthesis of pyrido[1,2-
a]benzimidazoles. The effects of substituents (R2) on the aniline
ring were examined first. Both electron-donating and electron-
withdrawing groups in the ortho (Table 2, 2l-2n) and para (Table
2, 2b-2g) positions relative to the aniline nitrogen were well
tolerated, and good to excellent yields of the corresponding
substituted pyrido[1,2-a]benzimidazoles were obtained (68-84%).
strong acid-mediated heterocycle synthetic procedures, the strategy
involving intramolecular C-H activation/C-heteroatom bond
formation provides a complementary approach to the synthesis of
heterocycles that is compatible with the increasing requirements
for environmentally benign and efficient processes.2 Although
metal-catalyzed nitrene insertion into C-H bonds is a well-
established methodology for formation of C-N bonds,3 intramo-
lecular amination via C-H activation was not realized until the
pioneering research work by Buchwald in 2005.4a Since then, an
increasing number of N-heterocycles, such as carbazoles,4 benz-
imidazoles,5 indazoles,6 indolines,7 and N-methoxylactams,8 have
been constructed by using this novel C-N bond-forming strategy.
In this context, palladium catalysts together with stoichiometric or
excess amounts of oxidants, such as Cu(OAc)2, AgOAc, PhI(OAc)2,
CeSO4, and/or F+, have been used predominantly.4,6-8 Much
cheaper copper salts along with dioxygen as the terminal oxidant
have been only rarely used in direct C-H activation/C-heteroatom
bond-forming processes,9 especially in intramolecular variants.5,10
Below, we report the discovery of copper-catalyzed intramolecular
C-H amination reactions of N-aryl-2-aminopyridines that produce
pyrido[1,2-a]benzimidazoles and involve the unprecedented coop-
erative action of an iron(III) salt11 and dioxygen as the terminal
oxidant.
Owing to their antibacterial,12 antitumor,13 and antiviral activi-
ties,14 considerable effort has been directed toward the synthesis
of pyrido[1,2-a]benzimidazoles. However, the methods developed
thus far suffer from the lengths of the preparative routes, the
formation of regioisomeric mixtures of products, limited substrate
scope, and/or unsatisfactory yields.15 As a result, an efficient
approach for the synthesis of these substances that has a wide
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J. AM. CHEM. SOC. 2010, 132, 13217–13219 13217

C O M M U N I C A T I O N S
Table 1. Optimization of the Reaction Conditionsa
A plausible reaction mechanism, especially one that highlights
the critical and unique role played by iron(III), was proposed based
on the following observations. First, a competition reaction using
excess amounts of Cu(OAc)2 was carried out. The yield of 2a
diminished dramatically to 58% when Fe(NO3)3 ·9H2O was absent,
even when 200 mol % of Cu(OAc)2 was employed under otherwise
identical conditions. This result indicates that reoxidation of Cu(I)
to Cu(II) is not or at least not the only role of iron(III). Second,
deuterium incorporation in the product 2a-D and recovered 1a-D
was monitored at the middle and end of reactions of the mono-
deuteriated substrate 1a-D under both iron and iron-free conditions
(Table 3). Deuterium incorporation in recovered 1a-D was found
to decrease to 70% after a reaction time of 2 h when iron(III) was
absent, while the deuterium content of the recovered reactant
remained unchanged (>95%) when the iron salt was present in the
reaction mixture. Analysis of the deuteration rate of 2a-D showed
that the process was associated with a primary H/D kinetic isotope
effect (kH/kD ) 2.4)16 when iron(III) was present. The results
demonstrate that the aromatic C-H activation reaction is reversible
and that H-D exchange takes place under the iron-free conditions.
In contrast, C-H bond cleavage is the rate-determining step and
the process is irreversible in the presence of iron(III).
cocatalyst
(equiv)c
solvent
(equiv)
time
(h)
yield
(%)d
entry
catalyst
1b
2b
3
4
5
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.2)
A (3.0)
A (3.0)
-
B (0.1)
C (0.1)
D (0.1)
B (0.1)
B (0.1)
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
12
12
20
7
5
4
trace
47
44
81
52
67
88
82
6
7e
8e
18
28
a Reaction conditions: 1a (0.50 mmol), solvent (1.0 mL), O2 balloon,
130 °C. b Under air. c A: Cu(OAc)2; B: Fe(NO3)3 ·9H2O; C: FeCl3; D:
Fe2(SO4)3. d Yield of isolated 2a. e 5.0 equiv of PivOH was added.
It is noteworthy that a bromo-substituent remained intact under these
reaction conditions (Table 2, 2g), an observation that suggests
further diversification of the process is possible. The reactions were
sluggish when electron-deficient m-chloro and m-fluoro substituted
substrates (1j and 1k) were employed. In these cases, an increase
in catalyst loading to 100 mol % was necessary in order to produce
the corresponding products 2j and 2k efficiently. In reactions in
which two regioisomeric products could be formed (Table 2,
2h-2k), only the less sterically hindered products were generated.
Table 3. Deuteration Study
Table 2. Synthesis of Substituted Pyrido[1,2-a]benzimidazolesa
time
(h)
2a-D
(%)b
deut. rate of
2a (%)c
1a-D
(%)b
deut. rate of
1a (%)c
cond.
A
B
A
B
2
2
18
18
65
16
88
27
71
55
70
33
29
81
0
>95
70
-
-
-
a Condition A: 1a-D (0.5 mmol, D% > 95%), Cu(OAc)2, 50 mol %,
Fe(NO3)3 ·9H2O 10 mol %. Condition B: same as condition A but
without Fe(NO3)3 ·9H2O. b Yield of isolated 2. c The deuteration rate
1
was determined by H NMR.
Finally, the relative reactivity of substrates with electron-rich
and electron-poor groups was examined.16 Substrates with electron-
donating groups at both of the meta and para positions of the aniline
ring were observed to react faster than those with electron-
withdrawing groups at the same positions. However, electron-
withdrawing groups in the meta position retarded the reaction rate
much more than those at the para position. The results suggest
that an electrophilic aromatic substitution (SEAr) mechanism is
likely operating in this process.18,5,10
a 0.50 mmol scale of 1, isolated yield of 2. b Cu(OAc)2 100 mol %.
Reactions of N-aryl-2-aminopyridines with substituents at all of
the four pyridine ring positions (R1) were also examined. When
the pyridine moiety was substituted with electron-withdrawing
groups, such as F, Cl, and CN, the starting materials cannot be
consumed completely under the standard reaction conditions. On
the other hand, substrates with methyl groups at all positions
undergo the reaction efficiently (Table 2, 2o-2q) except when a
methyl group is present at the position next to the pyridine ring
nitrogen (Table 2, 2r). In this instance, steric interference of the
adjacent methyl with coordination of copper to the pyridine nitrogen
might be responsible for the unexpectedly low yield observed.
Additionally, N-phenyl-2-aminoquinoline and N-phenyl-2-ami-
noisoquinoline were ideal substrates whose reactions led to the
benzo-fused pyrido[1,2-a]benzimidazoles 2s and 2t in good and
excellent yields, respectively.
Based on the above observations, the mechanisms depicted in
Scheme 2 are proposed for reactions in the presence and absence
of iron salts. In the absence of iron(III), a Cu(II) adduct A is formed
initially, followed by electrophilic aromatic substitution to form a
Cu(II) intermediate C. Reversible protonation of C occurs before
it is oxidized to a reactive Cu(III) intermediate D. Reductive
elimination delivers the product 2a with concurrent formation of
Cu(I), and Cu(II) is regenerated by O2 oxidation to close the
catalytic cycle.19
In the presence of iron(III), the Cu(II) adduct A is oxidized to a
more electrophilic Cu(III) intermediate E,20 which undergoes the
following electrophilic substitution process more readily. Elimina-
tion of the aromatic proton yields intermediate D via a six-
membered transition state F. The primary H/D kinetic isotope effect
9
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C O M M U N I C A T I O N S
noted above shows that this step is rate-limiting. Reductive
elimination then takes place quickly before reversible protonation
occurs.
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preparation of pyrido[1,2-a]benzimidazoles by using direct in-
tramolecular aromatic C-H amination of N-aryl-2-aminopyridines,
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Acknowledgment. We are grateful for the support of this work
by a Start-up Grant from Guangzhou Institutes of Biomedicine and
Health (GIBH), National Science Foundation of China (21072190)
and a grant-in-aid for scientific research from the Chinese Academy
of Sciences Innovation Grant (KSCXI-YW-10). We thank Dr.
Fayang Qiu for valuable discussions.
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Supporting Information Available: Experimental and characteriza-
tion details. This material is available free of charge via the Internet at
http://pubs.acs.org.
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