Copper-catalyzed aerobic oxidative C-H functionalization of substituted pyridines: Synthesis of imidazopyridine derivatives

Article abstract of DOI:10.1002/chem.201302737

A novel, efficient, and practical method for the synthesis of imidazopyridine derivatives has been developed through the copper-catalyzed aerobic oxidative C-H functionalization of substituted pyridines with N-(alkylidene)-4H-1,2,4-triazol-4-amines. The procedure occurs by cleavage of the N-N bond in the N-(alkylidene)-4H-1,2,4-triazol-4-amines and activation of an aryl C-H bond in the substituted pyridines. This is the first example of the preparation of imidazopyridine derivatives by using pyridines as the substrates by transition-metal-catalyzed C-H functionalization. This method should provide a novel and efficient strategy for the synthesis of other nitrogen heterocycles.

Full text of DOI:10.1002/chem.201302737

DOI: 10.1002/chem.201302737
À
Copper-Catalyzed Aerobic Oxidative C H Functionalization of Substituted
Pyridines: Synthesis of Imidazopyridine Derivatives
Jipan Yu,[a] Yunhe Jin,[a] Hao Zhang,[a] Xiaobo Yang,[a] and Hua Fu*[a, b]
À
Abstract: A novel, efficient, and practi-
cal method for the synthesis of imida-
zopyridine derivatives has been devel-
oped through the copper-catalyzed
the N N bond in the N-(alkylidene)-
4H-1,2,4-triazol-4-amines and activa-
tuted pyridines. This is the first exam-
ple of the preparation of imidazopyri-
dine derivatives by using pyridines as
the substrates by transition-metal-cata-
À
tion of an aryl C H bond in the substi-
À
À
aerobic oxidative C H functionaliza-
lyzed C H functionalization. This
À
Keywords: C H activation · cop-
per · homogeneous catalysis · nitro-
gen heterocycles · oxidation
tion of substituted pyridines with N-(al-
kylidene)-4H-1,2,4-triazol-4-amines.
The procedure occurs by cleavage of
method should provide a novel and ef-
ficient strategy for the synthesis of
other nitrogen heterocycles.
Introduction
the core structure of many drugs currently on the market.
Zolpidem (A) is the most widely applied drug in the world
for treating insomnia,[8] Alpidem (B) as a peripheral benzo-
diazepine receptor ligand is an anxiolytic,[9] Zolimidin (C)
acts as an anti-ulcer agent,[10] and Olprinone (D) as a phos-
phodiesterase 3 inhibitor is used for treating acute heart fail-
ure (Figure 1).[11] Accordingly, various efficient and useful
The pyridine unit occurs widely in various natural products,
and is a constituent of many pharmaceuticals and optical
materials. Its functionalization has attracted considerable at-
tention, however, because of the low reactivity of the p-elec-
tron-deficient pyridine skeleton, this remains a great chal-
lenge and halogenation and metalation are usually necessary
before the pyridine ring can be substituted.[1] Clearly, direct
À
C H functionalization of pyridines would be more economic
À
and practical. Recently, transition-metal-catalyzed C H
functionalization reactions have become the subject of in-
tensive studies,[2] and the transition-metal-catalyzed C H
À
functionalization of substituted pyridines has made signifi-
cant progress,[3] but unfortunately examples remain very lim-
ited. In 2010, Barluenga, Tomꢀs and co-workers reported an
efficient copper-catalyzed annulation of pyridines with
highly active alkenyldiazoacetates leading to indolizines.[4]
ImidazoACHTUNGTRENNUNG[1,2-a]pyridine derivatives have shown diverse bio-
logical and pharmaceutical activities,[5] for example, they ex-
hibit anticancer, antiviral, antiparasitic, and anti-HIV prop-
erties,[6] and some compounds have been used as NO syn-
thase and GABAA inhibitors, and l-DOPA and dopamine
Figure 1. Representative examples of imidazo
ed drugs (see ref. [5a]).
ACHTUNGTNER[NUNG 1,2-a]pyridines in market-
pro-drugs.[7] In particular, the imidazo
[1,2-a]pyridine unit is
approaches to imidazopyridine derivatives have been devel-
oped in which substituted 2-aminopyridines are usually em-
ployed as the starting materials.[5,12]
[a] J. Yu, Y. Jin, H. Zhang, X. Yang, Prof. Dr. H. Fu
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology
Compared with 2-aminopyridines, pyridines are more
readily available and inexpensive. To the best of our knowl-
edge, the annulation of pyridines to form imidazoACTHNUTRGNE[UNG 1,2-a]pyri-
(Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (P.R. China)
Fax: (+86)10-62781695
À
dine derivatives by transition-metal-catalyzed C H function-
alization has not been reported. In view of the low cost, low
toxicity, and high efficiency of copper catalysts,[13] herein we
report an efficient copper-catalyzed aerobic oxidative ap-
proach to the synthesis of imidazopyridine derivatives by
using readily available pyridines and N-(alkylidene)-4H-
1,2,4-triazol-4-amines (obtained from the reaction of 4-
amino-1,2,4-triazole with ketones[14]) in a cascade reaction
E-mail: fuhua@mail.tsinghua.edu.cn
[b] Prof. Dr. H. Fu
Key Laboratory of Chemical Biology (Guangdong Province)
Graduate School of Shenzhen, Tsinghua University
Shenzhen 518057 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302737.
16804
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16804 – 16808

FULL PAPER
À
that involves the cleavage of the N N bond and activation
effect of solvent was next investigated (compare entries 3
and 11–13), and DMF provided the best result (entry 3).
When the reaction temperature was changed to 80
(entry 14) or 1308C (entry 15), the yields decreased (com-
pare entries 3, 14, and 15). The catalytic efficiency was
lower when the reaction was performed in air (compare en-
tries 3 and 16) and no target product was observed in the
absence of oxygen (entry 17). Therefore the optimum condi-
tions for the copper-catalyzed aerobic oxidative synthesis of
À
of the pyridyl C H bond (Scheme 1).
imidazoACHTNUTRGNE[UNG 1,2-a]pyridines are as follows: 10 mol% CuI as the
catalyst in DMF as solvent at 1108C under an atmosphere
of oxygen (1 atm).
Having obtained the optimum reaction conditions, we in-
Scheme 1. Our Strategy for Synthesis of ImidazoACHTNUTRGNEUNG[1,2-a]pyridines.
vestigated the scope of the copper-catalyzed aerobic oxida-
À
tive C H functionalization of substituted pyridines 1 with
N-(alkylidene)-4H-1,2,4-triazol-4-amines
2
leading to
Results and Discussion
imidazo
G
the tested substrates provided moderate-to-good yields of
the product 3, the reaction efficiency being dependent on
electronic effects and steric hindrance. Pyridines with elec-
tron-donating substituents showed higher reactivity than
those with electron-withdrawing groups. For 3-methylpyri-
As shown in Table 1, the copper-catalyzed aerobic oxidative
reaction of pyridine (1a) with N-(1-phenylethylidene)-4H-
1,2,4-triazol-4-amine (2a) leading to 2-phenylimidazoACTHNUTRGNEU[GN 1,2-
À
dine, the copper-catalyzed aromatic C H functionalization
occurred at the 2- and 6-positions to give two isomers, the
isomer obtained by functionalization of the 2-position pre-
Table 1. Optimization of the copper-catalyzed aerobic oxidative reactions
of pyridine (1a) with N-(1-phenylethylidene)-4H-1,2,4-triazol-4-amine
(2a) leading to 2-phenylimidazoACHTUNGTRNEUNG
[1,2-a]pyridine (3a).[a]
À
dominating (entry 19). The aromatic C H functionalization
of isoquinoline selectively occurred at the a position be-
cause of high electronic density at the a-carbon atom
(entry 22). 2-Methylpyridine gave a lower yield due to steric
hindrance of the o-methyl group (entry 18).
Entry
Cat.
Solvent
T [oC]
Yield [%][b]
For the N-(1-arylethylidene)-4H-1,2,4-triazol-4-amines 2,
substrates with electron-withdrawing groups on the aromatic
ring afforded higher yields than those with neutral or elec-
tron-donating groups. The copper-catalyzed aerobic oxida-
tive reactions tolerated various functional groups, including
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CuCl
CuBr
CuI
Cu2O
CuCl2
CuBr2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
dioxane
toluene
DMF
DMF
DMF
DMF
110
110
110
110
110
110
110
110
110
110
110
110
110
80
47
55
63
21
41
36
8
17
13
0
27
11
trace
21
53
32[d]
0[e]
À
À
À
C Cl (Table 2, entries 4, 5, and 21), C Br (entry 6), and C
F bonds (entries 7–9), cyano (entry 10), trifluoromethyl
(entry 11), and nitro groups (entries 12, 13, 17, and 21), and
oxygen, sulfur, and nitrogen heterocycles (entries 14–16) in
the substrates. Interestingly, the reactions underwent pyri-
Cu
Cu
Cu(TFA)2
ACHTUNGTRENNUNG
T
[c]
ACHTUNGTRENNUNG
–
CuI
CuI
CuI
CuI
CuI
CuI
CuI
À
dine activation to form two C N bonds and therefore the
present method should provide a novel and useful strategy
for the synthesis of nitrogen heterocycles.
130
110
110
We attempted the synthesis of Zolimidin (C), an anti-
ulcer agent, on
a gram scale by using our method
[a] Reaction conditions: pyridine (1a, 5 mmol), N-(1-phenylethylidene)-
4H-1,2,4-triazol-4-amine (2a, 0.5 mmol), catalyst (0.05 mmol), solvent
(2 mL), oxygen atmosphere (1 atm), 80–1308C, 36 h. [b] Isolated yields.
[c] TFA=CF3COOÀ. [d] In air. [e] Under nitrogen atmosphere.
(Scheme 2). The reaction of pyridine (1a) with N-{1-[4-
(methylsulfonyl)phenyl]ethylidene}-4H-1,2,4-triazol-4-amine
(2r) under the standard conditions provided the target prod-
uct in a high yield (84%). Therefore the present method is
very effective for the synthesis of imidazo
with biological and pharmaceutical activities.
In an attempt to synthesize 3-substituted imidazo
ACHTUNGTREN[NUGN 1,2-a]pyridines
a]pyridine (3a) was chosen as the model to optimize the re-
action conditions, including the catalyst, solvent, and tem-
perature. Nine copper catalysts (10 mol% relative to the
amount of 2a) were first screened (entries 1–9) with DMF
as the solvent and oxygen as the oxidant at 1108C, CuI
showing the highest activity (entry 3). No product was ob-
served in the absence of a copper catalyst (entry 10). The
ACHTUNGTRENNUNG[1,2-
a]pyridines, 1-phenyl-N-(4H-1,2,4-triazol-4-yl)propan-1-
imine (2s) was treated with pyridine (1a) under the stan-
dard conditions (Scheme 3), but unfortunately the reaction
failed for steric hindrance of 2s, so the present method is
Chem. Eur. J. 2013, 19, 16804 – 16808
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H. Fu et al.
Table 2. Copper-catalyzed aerobic oxidative synthesis of imidazoACTHNUTRGNE[NUG 1,2-
Table 2. (Continued)
Entry
a]pyridines (3).[a]
2
3 (Yield [%][b]
)
12
13
Entry
1
2
3 (Yield [%][b]
)
14
15
2
3
4
5
6
16
17
18
2a
2a
19[c]
7
8
9
20
21
2a
2l
22
2a
[a] Reaction conditions: substituted pyridine 1 (2.5 mmol for entries 12,
13, and 17; 5 mmol for the others), N-(alkylidene)-4H-1,2,4-triazol-4-
amine 2 (0.5 mmol), CuI (0.05 mmol), DMF (2 mL), oxygen atmosphere
(1 atm), 1108C, 36 h. [b] Isolated yield. [c] Using 3-methylpyridine (1c)
as the substrate.
10
11
not suitable for the synthesis of 3-substituted imidazo
a]pyridines.
ACHTUNGTRENNUNG[1,2-
To explore the reaction mechanism of the copper-cata-
lyzed aerobic oxidative synthesis of imidazo[1,2-a]pyridines,
AHCTUNGTRENNUNG
the radical scavenger 2,2,6,6-tetramethylpiperidin-1-yloxyl
(TEMPO) was added to the reaction system of pyridine
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Synthesis of Imidazopyridine Derivatives
FULL PAPER
the alkenyl moiety in III affords V with the elimination of
4H-1,2,4-triazole (IV), and intramolecular cycloaddition of
V yields VI with the regeneration of the catalyst CuI. The
isomerization of VI leads to VII, and final oxidation of VII
by oxygen gives the target product 3.
Scheme 2. Copper-catalyzed aerobic oxidative synthesis of Zolimidin (C)
on a gram scale under the standard conditions.
Conclusion
We have developed a novel and efficient copper-catalyzed
À
aerobic oxidative C H functionalization of substituted pyri-
dines with N-(alkylidene)-4H-1,2,4-triazol-4-amines leading
to imidazoACTHNUTRGENUG[N 1,2-a]pyridine derivatives. The protocol uses in-
expensive CuI as the catalyst, economic and environmental-
ly friendly oxygen as the oxidant, and readily available sub-
stituted pyridines and N-(alkylidene)-4H-1,2,4-triazol-4-
amines as the starting materials, and the corresponding
Scheme 3. Treatment of 1-phenyl-N-(4H-1,2,4-triazol-4-yl)propan-1-imine
(2s) with pyridine (1a) under the standard conditions.
(1a) and N-(1-phenylethylidene)-4H-1,2,4-triazol-4-amine
(2a); the reaction was not affected by TEMPO (Scheme 4),
imidazoACTHNGUTER[NNUG 1,2-a]pyridine derivatives were obtained in moder-
ate-to-good yields. The reaction proceeds by cleavage of the
À
À
which shows that the cleavage of the N N bond in 2 does
N N bond in the N-(alkylidene)-4H-1,2,4-triazol-4-amines
À
not produce a radical intermediate during the synthesis of
and activation of an aryl C H bond in the substituted pyri-
dines. In summary, this method is a novel, efficient, and
practical approach to the synthesis of imidazopyridine deriv-
atives, which are biologically and pharmaceutically active
molecules. This is the first example of the preparation of
À
this type of compound by the transition-metal-catalyzed C
H functionalization of pyridines as substrates. We believe
that this strategy could be applied to the synthesis of other
nitrogen heterocycles.
Scheme 4. Copper-catalyzed aerobic oxidative reaction of pyridine (1a)
with N-(1-phenylethylidene)-4H-1,2,4-triazol-4-amine (2a) in the pres-
ence of TEMPO under the standard conditions.
imidazo
also isolated in the copper-catalyzed aerobic oxidative syn-
thesis of imidazo[1,2-a]pyridines and the reactions needed
the presence of oxygen. On the basis of the above observa-
tions, a possible mechanism for the synthesis of imidazo[1,2-
a]pyridines is proposed in Scheme 5. First, the isomerization
of N-(alkylidene)-4H-1,2,4-triazol-4-amine (2) gives I, coor-
dination of the copper catalyst (CuI) to I provides complex
II with the liberation of HI, and treatment of II with HI
leads to III. Nucleophilic attack of substituted pyridine 1 on
G
Experimental Section
General procedure for synthesis of compounds 3a–v and Zolimidin (C):
A 25 mL Schlenk tube was charged with a magnetic stirrer and DMF
(2.0 mL). Substituted pyridine 1 (2.5–5 mmol), N-(alkylidene)-4H-1,2,4-
triazol-4-amine 2 (0.5 mmol), and CuI (0.05 mmol, 9.5 mg) were added to
the tube. The tube was then sealed and the mixture stirred at 1108C for
36 h under oxygen (1 atm). The resulting mixture was cooled to room
temperature, the solvent was removed on a rotary evaporator, and the
residue was purified by column chromatography on silica gel using petro-
leum ether/ethyl acetate as eluent to give the desired target product. The
characterization data of the products can be found in the Supporting In-
formation.
Acknowledgements
The authors wish to thank the Nation-
al Natural Science Foundation of
China (Grant nos. 21172128, 21372139
and 21221062), and the Ministry of
Science and Technology of China
(Grant no. 2012CB722605) for finan-
cial support.
Scheme 5. Possible mechanism for the copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNTRGNEUNG[1,2-a]pyridines.
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À
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Received: July 14, 2013
Revised: August 28, 2013
Published online: October 21, 2013
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Chem. Eur. J. 2013, 19, 16804 – 16808