Copper-catalyzed aerobic oxidative intramolecular alkene C-H amination leading to N-heterocycles

Article abstract of DOI:10.1021/ol2013395

A copper-catalyzed aerobic oxidative intramolecular alkene C-H amination has been developed using readily available substituted 3-benzylidene-2-pyridin- 2-ylmethyl-2,3-dihydro-isoindol-1-ones as the starting materials, and the corresponding N-heterocycles

Full text of DOI:10.1021/ol2013395

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3694–3697
Copper-Catalyzed Aerobic Oxidative
Intramolecular Alkene CÀH Amination
Leading to N-Heterocycles
Juyou Lu,† Yibao Jin,‡ Hongxia Liu,‡ Yuyang Jiang,‡ and Hua Fu*,†
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R.
China, and Key Laboratory of Chemical Biology (Guangdong Province), Graduate
School of Shenzhen, Tsinghua University, Shenzhen 518057, P. R. China
fuhua@mail.tsinghua.edu.cn
Received May 18, 2011
ABSTRACT
A copper-catalyzed aerobic oxidative intramolecular alkene CÀH amination has been developed using readily available substituted
3-benzylidene-2-pyridin-2-ylmethyl-2,3-dihydro-isoindol-1-ones as the starting materials, and the corresponding N-heterocycles were obtained
in good to excellent yields. This method should provide a new and useful strategy for constructing N-heterocycles.
N-Heterocycles are ubiquitous in a variety of natural
products and biologically active molecules,1 and they have
been assigned as privileged structures in drug development
because N-heterocyclic moieties often exhibit improved
solubility and can facilitate the salt formation property,
both of which are important for oral absorption and
bioavailability.2 The isoindolinone skeleton is the core unit
of numerous naturally occurring substances,3 and their
derivatives have shown interesting biological properties.4
The 1,4-dihydropyrazine ring is a key structural feature of
some redox-active biological molecules (such as 1,5-dihy-
droflavin coenzymes5) and marine luciferins.6 Pyrazine
derivatives have been widely used in the fields of medicinal
chemistry for the elaboration of the skeletons of biologi-
cally active sites.7 However, synthesis of the combined
molecules of isoindolinone and 1,4-dihydropyrazine fra-
meworks (Figure 1) is not reported thus far. Therefore, we
want to make thiskind ofpolyN-heterocyclesusing readily
available starting materials, and the synthesized new mo-
lecules can be potentially biologically activity.
† Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry.
‡ Key Laboratory of Chemical Biology (Guangdong Province), Graduate
School of Shenzhen.
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r
10.1021/ol2013395
Published on Web 06/22/2011
2011 American Chemical Society

and used catalytically, and palladium-catalyzed “Wacker-
type” heterocylizations represent prominent examples of
this principle and find many uses in the synthesis of oxygen
and nitrogen heterocycles.15 During the past decade, there
have been remarkable advances in copper-catalyzed or-
ganic synthesis, and a wide scope of applications have
been investigated because of the low cost and toxicity of
copper catalysts and good functional tolerance of copper-
catalyzed methods.16 Recently, several examples for effi-
cient copper-catalyzed sp2 CÀH amination have been
reported,17 and the heterocycles have been constructed
via copper-promoted18 or copper/iron-cocatalyzed19 arene
sp2 CÀH activation strategy using ideal dioxygen as the
oxidant.20 Herein, we report a novel copper-catalyzed
aerobic oxidative intramolecular alkene CÀH amination
leading to N-heterocycles under air.
Figure 1. Structure of conjugate containing isoindolinone and
1,4-dihydropyrazine frameworks.
The development of transition-metal-catalyzed reac-
tions for the formation of heterocycles continues to be an
active area of research.8 However, the precursors in the
traditional methods needed possession of the correspond-
ing functional groups or prefunctionalization before the
synthesis of N-heterocycles. Recently, the direct functio-
nalizationof CÀH bonds hasmade progress,9 and someN-
heterocycles, such as carbazoles,10 benzimidazoles,11
indazoles,12 indolines,13 and N-methoxylactams,14 have
been constructed through a CÀH activation/CÀN bond-
forming strategy, and most of the methods used expensive
palladium-, rhodium-, and ruthenium-based catalysts
although they were very efficient. The use of transition-
metal electrophiles in alkene heterocyclization reactions is
attractive because facile cleavage of the metalÀcarbon
bond often enables the metal electrophile to be regenerated
Table 1. Copper-Catalyzed CÀH Amination of 3-Benzylidene-
2-pyridin-2-ylmethyl-2,3-dihydro-isoindol-1-one (1a) Leading
to N-Hetercycle (2a) under Air: Optimization of Conditionsa
temp
yield
(%)b
entry
cat.
acid
solvent
(°C)
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1
CuI
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
AcOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
100
100
100
100
100
100
100
100
100
100
100
100
110
110
110
110
72
54
2
CuBr
CuCl
Cu2O
52
3
48
4
trace
40
5
Cu(OAc)2
6
Cu(O2CCF3)2
68
7
CuSO4 5H2O
63
3
8
CuCl2
trace
trace
trace
33
9
CuBr2
10
11
12
13
14
15
16
17
18
CuO
Cu
À
0
Cu(O2CCF3)2
83
CuSO4 5H2O
69
3
Cu(O2CCF3)2
Cu(O2CCF3)2
Cu(O2CCF3)2
Cu(O2CCF3)2
71
78
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CF3COOH
À
0
110
0
a Reaction conditions: 3-benzylidene-2-pyridin-2-ylmethyl-2,3-dihy-
droisoindol-1-one (1a) (0.5 mmol), catalyst (0.1 mmol), acid (1.5 mmol),
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Org. Lett., Vol. 13, No. 14, 2011
3695

Table 2. Copper-Catalyzed Aerobic Oxidative Intramolecular Alkene CÀH Amination Leading to N-Heterocyclesa
a Reaction condition: 1 (0.5 mmol), catalyst (0.1 mmol), PivOH (1.5 mmol), DMF (2 mL) in a flask under air. b Isolated yield.
3696
Org. Lett., Vol. 13, No. 14, 2011

At first, the substituted 3-methyleneisoindolin-1-ones
(1) were prepared through copper-catalyzed cascade reac-
tions of 2-bromobenzamides with terminal alkynes in
DMF in sealed Schlenk tubes at 80 °C according to the
previous procedure,21 and they were used as the substrates
in this work. Here, 3-benzylidene-2-pyridin-2-ylmethyl-2,3-
dihydro-isoindol-1-one (1a) was used as the model substrate
to optimize reaction conditions including catalysts, acids (as
additives), solvents, and reaction temperatures under air
(1 atm). As shown in Table 1, various copper salts (0.2 equiv)
were tested in the presence of 3 equiv of pivalic acid (relative
to amount of 1a) inDMFat100°Cunderair(entries1À11),
Scheme 1. Possible Mechanism for Copper-Catalyzed Aerobic
Oxidative Intramolecular Alkene CÀH Amination Leading to
N-Heterocycles (2)
and Cu(O2CCF3)2 and CuSO4 5H2O provided higher
3
yields (entries 6 and 7). The yields increased when the
temperature was raised to 110 °C from 100 °C, and Cu-
(O2CCF3)2 displayed more efficiency (see entries 13 and 14).
The yield decreased when DMSO replaced DMF as the
solvent (entry 15). We attempted other acids, trifluoroacetic
acid and acetic acid (entries 16 and 17), and they were
inferior to pivalic acid (compare entries 13, 16, and 17). No
target product was found in the absence of acid (entry 18).
The scope on the copper-catalyzed intramolecular CÀH
amination of 1 leading to N-hetercycles (2) was investi-
gated under the optimized conditions using 20 mol % of
Cu(O2CCF3)2 as the catalyst, 3 equiv of pivalic acid as the
additive (relative to amount of 1), and DMF as the solvent.
As shown in Table 2, the corresponding target products
were obtained in good to excellent yields for the examined
substrates at 100 or 110 °C. The reaction temperature
remained at 100 °C when R1 was halo substituents
(entries 15À22), and a slightly lower temperature could
reduce formation of side products. For R1 and R2 sub-
stituents, the substrates containing electron-donating
groups provided slightly higher yields than those contain-
ing electron-withdrawing groups. The copper-catalyzed
intramolecular CÀH amination showed the tolerance of
the functional groups in the substrates including ether
(entries 4, 9, 11À14, 17, and 21), CÀF bond (entries 5,
10, 18, and 22), CÀCl bond (entries 15À18), and CÀBr
bond (entries 19À22).
A possible mechanism for copper-catalyzed aerobic
oxidative intramolecular alkene CÀH amination is sug-
gested in Scheme 1. Coordination of the pyridine ring in 1
with Cu(O2CCF3)2 forms I, and isomerization of the
pyridine ring22 and the following complexationwithCu(II)
yields II releasing CF3COOH (TFA). Further intramole-
cular addition of the alkene CdC bond23 in II provides III,
and oxidation of III with oxygen in air in the presence of
acid gives 2 leaving a Cu(II) catalyst.
In summary, we have developed an efficient copper-
catalyzed aerobic oxidative intramolecular alkene CÀH
amination leading to N-heterocycles. The protocol uses
cheap and readily available Cu(O2CCF3)2 as the catalyst,
substituted 3-methyleneisoindolin-1-ones as the starting
materials, and economical and environment friendly air as
the oxidant, and the corresponding N-heterocycles were
obtained in good to excellent yields. To the best of our
knowledge, this can be the first example of constructing N-
heterocycles via copper-catalyzed aerobic oxidative intra-
molecular alkene CÀH amination. This method should
provide a new and useful strategy for constructing N-
heterocycles.
Acknowledgment. The authors wish to thank the Na-
tional Natural Science Foundation of China (Grant No.
20972083) and the Ministry of Science and Technology of
China (2009ZX09501-004) for financial support.
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Supporting Information Available. Synthetic proce-
dures, characterization data, and 1H, 13C NMR spectra
of these synthesized compounds. This material is
available free of charge via the Internet at http://
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