Cu-catalyzed direct C-H amination of 2-alkylazaarenes with azodicarboxylates via nucleophilic addition

Article abstract of DOI:10.1016/j.tetlet.2012.12.055

An efficient Cu-catalyzed C-H amination of 2-alkylazaarenes with azodicarboxylates has been developed through nucleophilic addition of sp ³C-H bond to unsaturated nitrogen-nitrogen double bond. It provides an easy access to azaarene-containing

Full text of DOI:10.1016/j.tetlet.2012.12.055

Tetrahedron Letters 54 (2013) 711–714
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Cu-catalyzed direct C–H amination of 2-alkylazaarenes with azodicarboxylates
via nucleophilic addition
⇑
Bo Qian, Lei Yang, Hanmin Huang
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient Cu-catalyzed C–H amination of 2-alkylazaarenes with azodicarboxylates has been developed
through nucleophilic addition of sp3C–H bond to unsaturated nitrogen–nitrogen double bond. It provides
an easy access to azaarene-containing hydrazines from simple and easily available starting materials.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 12 October 2012
Revised 3 December 2012
Accepted 14 December 2012
Available online 21 December 2012
Keywords:
Copper catalysis
C–H amination
2-Alkylazaarenes
Nucleophilic addition
C–H functionalization
Introduction
with great efficiency and selectivity via nucleophilic addition. In
light of these initial findings, we decided to take one further step
The elaboration of a new catalytic system for C–N bond con-
struction from simple starting materials, leading to complex
amines, remains one of the major challenges in organic synthesis.1
Among many documented methods for C–N bond formation, the
activation of inert C–H bond of hard nucleophiles and subse-
quently nucleophilic addition of C–H bond to unsaturated nitro-
gen-containing chemical bonds would be an attractive strategy
for the synthesis of amines from simple starting materials.2 For
the success of such a catalytic process, the development of efficient
catalytic method for conversion of a hard nucleophile to an active
soft nucleophile via direct C–H activation and identifying a proper
nitrogen-containing electrophile is a prerequisite.
Functionalized pyridines and related azaarenes, which are
important heteroarenes, play increasingly important roles in
natural compound synthesis and drug discovery.3 Consequently,
the development of mild, general, and efficient methods for direct
C–H functionalization of pyridine and other azaarene cores has
stimulated tremendous research efforts. In contrast, little progress
has been made toward the functionalized sp3C–H bond of the
alkylazaarenes.4 In this context, our group has developed an
efficient methodology for activating benzylic C–H bond of 2-al-
kyl-substituted azaarenes and subsequently transforming related
2-alkylazaarenes into active nucleophiles under neutral conditions.
This strategy has enabled the construction of various C–C bonds
in developing new synthetic protocols for direct functionalization
of 2-alkylazaarenes by this strategy. To this end, we turned our
attention toward the construction of C–N bond via selective C–H
cleavage and nucleophilic addition. Herein, we report an efficient
copper-catalyzed nucleophilic addition of sp3C–H bond to azodi-
carboxylates under mild neutral conditions.5
Azodicarboxylates are widely used as electrophiles for C–N
bond formation reactions via nucleophilic addition.6 Although
many kinds of soft nucleophiles have been used as coupling part-
ners for the corresponding nucleophilic addition reactions with
azodicarboxylates under transition-metal-catalyzed or metal-free
conditions, the direct incorporation of hard nucleophiles to this
kind of nitrogen source is still limited. Hence, inspired by our pre-
vious results and other works,7 we envisaged that the C–N bond
formation reaction would be realized by the reaction of 2-alkylaz-
aarenes with azodicarboxylates under proper reaction conditions,
affording the corresponding hydrazine-containing functionalized
heterocycles. As shown in Figure 1, the transformation might pro-
ceed via an active metal enamide species C, which would be
dynamically formed when the acidity of the benzylic proton was
enhanced by a suitable metal catalyst.
Results and discussion
At first, on the basis of our previous work, we examined the fea-
sibility of the reaction between 2,6-lutidine 1a and diisopropyl
azodicarboxylate 2a with Lewis acid as catalyst.8 To our delight,
⇑
Corresponding author. Tel.: +86 931 4968326; fax: +86 931 4968129.
E-mail address: hmhuang@licp.cas.cn (H. Huang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.055

712
B. Qian et al. / Tetrahedron Letters 54 (2013) 711–714
was conducted using 5 mol % of Cu(OTf)2 as catalyst and dioxane
[M]
N
R
R
R
as solvent under argon atmosphere at 120 °C for 24 h (Table 1, en-
try 1). Encouraged by this result, we investigated the reaction con-
ditions in detail, and the results were summarized in Table 1. An
initial study of solvents with different polarity was conducted
and the results showed that the reaction performed well in non-
polar solvents. For example, 63% yield of 3aa was obtained when
xylene was used as solvent, which was much better than that ob-
tained in other polar solvents. Thus, xylene was determined to be
the most appropriate solvent for this transformation.
Subsequently, a variety of Lewis acid catalysts, which were
effective for this type of reactions in other cases, were screened,7b
and the results were shown in Table 2. Among the Lewis acid cat-
alysts screened, the Cu(OTf)2 demonstrated the best catalytic effi-
ciency for giving the desired product 3aa with 63% yield in the
R1
R1
R1
N
H
N
N
A
B
C
[M]
COOR2
COOR2
N
R
R2OOC
2
N
N
NH
R1 COOR2
3
Figure 1. Reaction of 2-alkylazaarenes with azodicarboxylates.
the reaction could occur under the catalysis of Cu(OTf)2, and 35%
yield of the desired product 3aa was obtained when the reaction
Table 1
Optimization of reaction conditions with solventa
COOiPr
COOiPr Cu(OTf)2 (5 mol%)
Solvent, 120 oC, 24 h
N
COOiPr
N
N
iPrOOC
N
N
H
N
3aa
1a
2a
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Dioxane
CH3CN
DMF
35
22
23
NR
43
47
35
53
63
57
44
54
iPrOH
MCPE
THF
CH2Cl2
PhCH3
Xylene
PhCF3
Mesitylene
PhCl
9
10
11
12
a
Reaction conditions: 1a (0.75 mmol), 2a (0.30 mmol), Cu(OTf)2 (0.015 mmol), solvent (1.5 mL), 120 °C for 24 h.
Isolated yield.
b
Table 2
Optimization of reaction conditionsa
COOiPr
Metal / Ligand
Xylene, 120 oC, 24 h
COOiPr
COOiPr
N
N
N
iPrOOC
N
N
H
N
2a
Catalyst
3aa
1a
Entry
Ligand
Yieldb (%)
1
2
Zn(OTf)2
AlCl3
—
—
6
40
Trace
63
14
23
42
21
24
55
75
69
45
NR
3
4
5
6
7
8
9
10
11
12
13
14
Sc(OTf)3
Cu(OTf)2
Cu(SbF6)2
Cu(BF4)2
Cu(OTs)2
Cu(OAc)2
Cu(ClO4)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
—
—
—
—
—
—
—
—
DPPE
DPPP
DPPPen
DPPHex
—
a
Reaction conditions: 1a (0.75 mmol), 2a (0.30 mmol), metal catalyst (0.015 mmol), ligand (0.018 mmol), xylene
(1.5 mL), 120 °C for 24 h.
b
Isolated yield.

B. Qian et al. / Tetrahedron Letters 54 (2013) 711–714
713
Table 3
Substrate scope of the reactiona
COOR2
COOR2
Cu(OTf)2 / DPPP
Solvent, 120 oC, 24 h
R
COOR2
N
N
R
N
R1
R2OOC
N
N
H
N
R1
2
3
2a: R2 = iPr, 2b: R2 = Et
1
COOiPr
COOEt
COOEt
N
COOiPr
N
COOEt
N
COOEt
N
N
H
N
N
H
N
N
N
H
3aa 75%a
3ab 74%a
3bb 63%b
COOEt
N
COOEt
N
COOEt
N
COOEt
COOEt
COOEt
N
N
H
N
H
N
N
H
Ph
3cb 36%b
3db 47%b
3eb 50%b
Br
COOEt
COOEt
COOEt
N
COOEt
COOEt
N
COOEt
N
COOEt
Ph
N
N
H
N
N
H
N
N
N
H
3gb 43%c
3fb 37%b
3hb 71%c
COOEt
COOEt
N
COOEt
N
COOEt
N
COOEt
N
Cl
N
N
H
N
N
H
H
OMe
OH
3ib 70%c
3kb 49%c
3jb 51%c
N
COOEt
COOEt
COOEt
N
COOEt
N
COOEt
N
COOEt
N
N
H
N
N
H
N
N
H
3nb 49%c
3lb 70%c
3mb 64%c
a
b
c
Reaction conditions: 1 (0.75 mmol), 2 (0.3 mmol), Cu(OTf)2 (0.015 mmol), DPPP (0.018 mmol), xylene (1.5 mL), 120 °C, 24 h.
Cu(OTf)2 (0.03 mmol), DPPP (0.036 mmol) in the mixture of toluene (1.0 mL) and THF (0.5 mL).
Cu(OTf)2 (0.003 mmol), DPPP (0.0036 mmol), in the mixture of toluene (1.0 mL) and THF (0.5 mL).
absence of ligand (Table 2, entry 4). Further experiments con-
ducted for searching more active catalysts by changing the count-
eranion of the copper salts were proved to be unsuccessful.
However, the efficiency of this reaction could be improved when
DPPP was used as a ligand.9 As a result, with Cu(OTf)2/DPPP as cat-
alyst, the yield of the desired product could be increased to 75%
(Table 2, entry 11). Finally, control reactions demonstrated that
the desired product was not observed at all in the absence of cat-
alyst (Table 2, entry 14).
With the optimized reaction conditions in hand, we next ex-
plored the scope of the present reaction and a variety of azaa-
rene-containing hydrazines 3 were prepared (Table 3). First,
diethyl azodicarboxylate 2b also demonstrated good reactivity in
this transformation to give the corresponding product 3ab in 74%
yield under the optimized conditions.10 A range of 2-methylpyri-
dines (1b, 1e, and 1f), 2-ethylpyridine (1c), and 2-benzylpyridine
(1d) were subjected to the reaction with diethyl azodicarboxylate
2b as an electrophile and the corresponding products (3bb–3fb)
were obtained in good yields. Besides the substituted 2-alkylpyri-
dines, the substituted 2-alkylquinolines could also react with
diethyl azodicarboxylate 2b even in the absence of metal catalyst
affording the desired addition products in lower yields. But higher
activity was always observed in the presence of catalyst. Thus, in
order to get higher yields, the corresponding reactions were con-
ducted in the presence of 1 mol % of Cu(OTf)2/DPPP under the mod-
ified conditions. Under the modified conditions, the hydrazine
group could be successfully incorporated into the substituted qui-
naldines. The chloro and bromo group can survive the reaction
conditions to give the corresponding functionalized hydrazines
such as 3hb and 3ib in good yield. The ability to tolerate the incor-
poration of additional halogen substituents is useful for further
functionalization with transition metal catalysis. Inclusion of
additional free OH-substituent in the substrates was also possible,
leading to a hydroxyl-substituted product (3jb), which was advan-
tageous to further transformation too. Under the same reaction
conditions, 2-ethylquinoline and 2-methylquinoxaline were also
competent in this transformation to give the desired products
3mb and 3nb in good yields.

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In summary, we have successfully developed a new protocol of
copper-catalyzed selective C–H cleavage and subsequently nucleo-
philic addition of 2-alkylazaarenes to azodicarboxylates affording
azaarene-containing hydrazines. The reactions proceed with good
yield and give an easy access to azaarene-containing hydrazines
from simple and easily available starting materials.
Acknowledgments
5. During the preparation of this manuscript,
a similar work based on our
Financial support provided by the National Natural Science
Foundation of China (21172226, 21133011, and 21222203), and
Chinese Academy of Sciences is gratefully acknowledged.
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Supplementary data
Supplementary data (experimental procedures and full charac-
terization of all products including 1H, 13C NMR and HRMS spectra)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.12.055.
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9. A series of monophosphine ligands and several nitrogen-containing ligands
were also screened and lower reactivities were observed. See Supplementary
data for details.
10. Other azo compounds such as, azobenzene and azopyridine, have been tested
in this reaction, but no desired products were observed.